System and method for distinguishing between hypoglycemia and hyperglycemia using an implantable medical device

ABSTRACT

Techniques are described for detecting and distinguishing among ischemia, hypoglycemia or hyperglycemia based on intracardiac electrogram (IEGM) signals. In one technique, these conditions are detected and distinguished based on an analysis of: the interval between the QRS complex and the peak of a T-wave (QTmax), the interval between the QRS complex and the end of a T-wave (QTend), alone or in combination with a change in ST segment elevation. By exploiting QTmax and QTend in combination with ST segment elevation, changes in ST segment elevation caused by hypo/hyperglycemia can be properly distinguished from changes caused by cardiac ischemia. In another technique, hyperglycemia and hypoglycemia are predicted, detected and/or distinguished from one another based on an analysis of the amplitudes of P-waves, QRS-complexes and T-waves within the IEGM. Appropriate warning signals are delivered and therapy is automatically adjusted.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-in-Part of U.S. patent applicationSer. No. 11/043,612, of Gill et al., filed Jan. 25, 2005, entitled“System and Method for Distinguishing Among Cardiac Ischemia,Hypoglycemia And Hyperglycemia Using an Implantable Medical Device”(Atty. Docket No. A05P1007).

FIELD OF THE INVENTION

The invention generally relates to implantable medical devices such aspacemakers and implantable cardioverter/defibrillators (ICDs) and, inparticular, to techniques for detecting cardiac ischemia, hypoglycemiaand hyperglycemia using such devices and, more specifically, totechniques for more effectively detecting and distinguishinghypoglycemia from hyperglycemia.

BACKGROUND OF THE INVENTION

Cardiac ischemia is a condition whereby heart tissue does not receiveadequate amounts of oxygen and is usually caused by a blockage of anartery leading to heart tissue. If sufficiently severe, cardiac ischemiaresults in an acute myocardial infarction (AMI), also referred to as aheart attack. With AMI, a substantial portion of heart muscle ceases tofunction because it no longer receives oxygen, usually due tosignificant blockage of the coronary artery. Generally, AMI occurs whenplaque (such as fat, cholesterol, and calcium) builds up and thenruptures in the coronary artery, allowing a blood clot or thrombus toform. Eventually, the blood clot completely blocks the coronary arteryand so heart tissue beyond the blockage no longer receives oxygen andthe tissue dies. In many cases, an AMI proves fatal because too muchtissue is damaged to allow continued functioning of the heart muscle.Indeed, AMI is a leading cause of death here in the United States andworldwide. In other cases, although the AMI itself is not fatal, itstrikes while the victim is engaged in potentially dangerous activities,such as driving vehicles or flying airplanes, and the severe pain andpossible loss of consciousness associated with AMI results in fatalaccidents. Even if the victim survives the AMI, quality of life maythereafter be severely restricted.

Often AMI is preceded by episodes of cardiac ischemia that are notsufficiently serious to cause actual permanent injury to the hearttissue. Nevertheless, these episodes are often precursors to AMI.Episodes of cardiac ischemia may also trigger certain types ofarrhythmias that may prove fatal, particularly ventricular fibrillation(VF) wherein the ventricles of the heart beat chaotically, resulting inlittle or no net flow of blood from the heart to the brain and otherorgans. Indeed, serious episodes of cardiac ischemia (referred to hereinas acute myocardial ischemia) typically result in either a subsequentAMI or VF, often within one to twenty-four four hours, sometimes withinonly a half an hour or less. Accordingly, it would be highly desirableto provide a technique for reliably detecting acute myocardial ischemiaso that the victim may be warned and medical attention sought. Ifproperly warned, surgical procedures may be implemented to locate andremove the growing arterial blockage or anti-thrombolytic medicationsmay be administered. At the very least, advanced warning would allow thevictim to cease activities that might result in a fatal accident.Moreover, in many cases, AMI or VF is triggered by strenuous physicalactivities and so advanced warning would allow the victim to cease suchactivities, possibly preventing AMI or VF from occurring.

Many patients at risk of cardiac ischemia have pacemakers, ICDs or othermedical devices implanted therein. Accordingly, techniques have beendeveloped for detecting cardiac ischemia using implanted medicaldevices. In particular, techniques have been developed for analyzingintracardiac electrogram (IEGM) signals in an effort to detect cardiacischemia. See, as examples, the following U.S. Pat. Nos. 5,113,869 toNappholz; 5,135,004 to Adams et al.; 5,199,428 to Obel et al.; 5,203,326to Collins; 5,313,953 to Yomtov et al; 6,501,983 to Natarajan, et al.;6,016,443, 6,233,486, 6,256,538, and 6,264,606 to Ekwall; 6,021,350 toMathson; 6,112,116 and 6,272,379 to Fischell et al; 6,128,526, 6,115,628and 6,381,493 to Stadler et al; and 6,108,577 to Benser. Most IEGM-basedischemia detection techniques seek to detect ischemia by identifyingchanges in the elevation of the ST segment of the IEGM that occur duringcardiac ischemia. The ST segment represents the portion of the cardiacsignal between ventricular depolarization (also referred to as an R-waveor QRS complex) and ventricular repolarization (also referred to as aT-wave). The QRS complex usually follows an atrial depolarization (alsoreferred to as a P-wave.) Strictly speaking, P-waves, R-waves andT-waves are features of a surface electrocardiogram (EKG). Forconvenience and generality, herein the terms R-wave, T-wave and P-waveare used to refer to the corresponding internal signal component aswell.

A significant concern with any cardiac ischemia detection technique thatrelies on changes in the ST segments is that systemic influences withinthe patient can alter the ST segment. For example, hypoglycemia (lowblood sugar levels) and hyperglycemia (high blood sugar levels) can bothaffect ST segment elevation. In addition, electrolyte imbalance, such ashypokalemia (low potassium levels) or hyperkalemia (high potassiumlevels) can affect the ST segment. Certain anti-arrhythmic drugs canalso affect the ST-segment.

Accordingly, alternative techniques for detecting cardiac ischemia havebeen developed, which do not rely on ST segment elevation. One suchtechnique is set forth in U.S. patent application Ser. No. 10/603,429,entitled “System And Method For Detecting Cardiac Ischemia Using AnImplantable Medical Device”, of Wang et al., filed Jun. 24, 2003, whichis incorporated by reference herein. Rather than examine the ST segment,the technique of Wang et al. instead examines post-T-wave segments, i.e.that portion of the cardiac signal immediately following the T-wave. Inone example, the onset of cardiac ischemia is identified by detecting asharp falling edge within post-T-wave signals. A warning is thenprovided to the patient. The warning preferably includes both aperceptible electrical notification signal applied directly tosubcutaneous tissue and a separate warning signal delivered viashort-range telemetry to a handheld warning device external to thepatient. After the patient feels the internal warning signal, he or sheholds the handheld device near the chest to receive the short-rangetelemetry signal, which provides a textual warning. The handheld warningdevice thereby provides confirmation of the warning to the patient, whomay be otherwise uncertain as to the reason for the internally generatedwarning signal. Another technique for detecting cardiac ischemia basedon T-waves is set forth in U.S. patent application Ser. No. 10/603,398,entitled “System And Method For Detecting Cardiac Ischemia Based OnT-Waves Using An Implantable Medical Device”, of Min et al., filed Jun.24, 2003, which is also incorporated by reference herein. With thetechnique of Min et al., cardiac ischemia is detected based either onthe total energy of the T-wave or on the maximum slope of the T-wave.Again, if ischemia is detected, a warning signal is provided to thepatient.

Hence, various cardiac ischemia detection techniques have been developedthat exploit T-waves. Although these techniques are effective, it isdesirable to provide still other T-wave-based ischemia detectiontechniques. It is also desirable to provide techniques that exploitdeviations in the ST segment as well as changes in T-waves to providefurther improvements cardiac ischemia detection. In particular, it ishighly desirable to identify particular changes in T-waves that can beused to distinguish deviations in the ST segment caused by cardiacischemia from changes caused by hypoglycemia or hyperglycemia or othersystemic affects so as to improve the reliability and specificity of STsegment-based ischemia detection.

Although the detection of cardiac ischemia is of paramount importancesince cardiac ischemia may be a precursor to a potentially fatal AMI orVF, it is also highly desirable to detect hypoglycemia or hyperglycemia,particularly within diabetic patients. Indeed, hypoglycemia is believedto be the cause of death in about three percent of insulin-treateddiabetic patients. The putative mechanism for death due to hypoglycemiais a hypoglycemia-induced prolongation of the QT interval of theintracardiac electrogram (IEGM), which increases the risk of malignantventricular tachycardia. See, for example, Eckert et al., “HypoglycemiaLeads to an Increased QT Interval in Normal Men”, Clinical Physiology,1998, Volume 18, Issue 6, Page 570 and also Heller, “Abnormalities ofthe Electrocardiogram during Hypoglycaemia: The Cause of the Dead in BedSyndrome”, Int. J. Clin. Pract. Suppl. 2002 July; (129): 27-32. Notethat QT interval represents the portion of the IEGM between thebeginning of ventricular depolarization and the peak of ventricularrepolarization.

Hypoglycemia is also a serious and frequent problem in patientssuffering hyperinsulinism, wherein the body generates too much insulin,thereby triggering episodes of hypoglycemia even if an otherwisesufficient amount of sugar or other glucose-generating substances areingested. Medications appropriate for addressing hyperinsulinismincluded sulfonylureas, meglitinides, biguanides, thiazolidinediones, oralpha glucosidase inhibitors.

In adults, if not treated properly, severe hypoglycemia may result incoma and irreversible brain damage. McCarthy et al., “Mild hypoglycemiaand impairment of brain stem and cortical evoked potentials in healthysubjects.” Department of Pediatrics, Yale University School of Medicine,New Haven, Conn. 06510.

Even in cases where hypoglycemia does not cause severe consequences, itis often the limiting factor in achieving good glycemic control inpatients with diabetes, particular insulin-depended diabetics. In thisregard, patients sometimes refrain from taking prescribed dosages ofinsulin for fear that the insulin might trigger an episode ofhypoglycemia, which can be unpleasant. Failure to take the prescribedinsulin prevents the patient from maintaining glycemic levels within ahealthy range, thus often leading to additional health problems.

Hyperglycemia, in contrast, is a condition characterized by abnormallyhigh blood glucose levels. Often, hyperglycemia arises due to a lack ofinsulin within insulin-dependent diabetics. Hyperglycemia withindiabetics can lead to ketoacidosis (i.e. diabetic coma), which can befatal. Briefly, ketoacidosis occurs if the body lacks sufficient insulinto properly process the high blood glucose levels associated withhyperglycemia. Without sufficient insulin, the body cannot processglucose for fuel and hence breaks down fats to use for energy, yieldingketones as waste products. However, the body cannot tolerate largeamounts of ketones and tries to eliminate the ketones through urine.Often, though, the body cannot eliminate the ketones and hence ketonesbuild up in the blood leading to ketoacidosis. Excessively high ketonelevels in the blood can be fatal.

Diabetic patients, hence, need to frequently monitor blood glucoselevels to ensure that the levels remain within acceptable bounds and,for insulin dependent diabetics, to determine the amount of insulin thatmust be administered. Conventional techniques for monitoring bloodglucose levels, however, leave much to be desired. One conventionaltechnique, for example, requires that the patient draw blood, typicallyby pricking the finger. The drawn blood is then analyzed by a portabledevice to determine the blood glucose level. The technique can bepainful and therefore can significantly discourage the patient fromperiodically checking blood glucose levels. Moreover, since an externaldevice is required to analyze the blood, there is the risk that thepatient will neglect to keep the device handy, preventing periodic bloodglucose level monitoring. For insulin-dependent diabetics, failure toproperly monitor blood glucose levels can result in improper dosages ofinsulin causing, in extreme cases, severe adverse health consequencessuch as a ketoacidotic diabetic coma, which can be fatal. Accordingly,there is a significant need to provide reliable hypo/hyperglycemiadetection techniques, which do not rely on the patient to monitoring hisor her own glucose levels and which does not require an externalanalysis device.

In view of the many disadvantages of conventional external blood glucosemonitoring techniques, implantable blood glucose monitors have beendeveloped, which included sensors for mounting directly within the bloodstream. However, such monitors have not achieved much success as theglucose sensors tend to clog over very quickly. Thus, an implantabledevice that could continually and reliably measure blood glucose levelswithout requiring glucose sensors would be very desirable. Moreover, aswith any implantable device, there are attended risks associated withimplanting the blood glucose monitor, such as adverse reactions toanesthetics employed during the implantation procedure or the onset ofsubsequent infections. Hence, it is desirable to provide for automatichypo/hyperglycemia detection using medical devices that would otherwiseneed to be implanted anyway, to thereby minimize the risks associatedwith the implantation of additional devices. In particular, for patientsalready requiring implantation of a cardiac stimulation device, such asa pacemaker or ICD, it is be desirable to exploit features of electricalcardiac signals.

It is now known that hypoglycemia can be detected based on observationof changes in the QT interval observed within an ECG (based on studiesinvolving experimental hypoglycemia within adults with type 1 diabetes,i.e. insulin-dependent diabetes), as well as based on observation ofdispersion of QT intervals within the ECG (based on studies involvingexperimental hypoglycemia within adults with type 2 diabetes, i.e.non-insulin dependent diabetes.) See, e.g., Landstedt-Hallin et al.,“Increased QT dispersion during hypoglycaemia during hypoglycaemia inpatients with type 2 DM.” Studies in diabetics have also shown thathypoglycemia can be detected based on observation of a significantlengthening of the QTc interval occurring during spontaneous nocturnalhypoglycemia. See, Robinson et al., “Changes In Cardiac RepolarizationDuring Clinical Episodes Of Nocturnal Hypoglycaemia In Adults With Type1 Diabetes” Diabetologia. February 2004; 47(2):312-5. Epub 08 Jan. 2004.The QTc interval is an adjusted version of the QT interval that has beencorrected to a heart rate of 60 beats per minute (bpm). See, also, U.S.Pat. No. 6,572,542 to Houben, et al., entitled “System and Method forMonitoring and Controlling the Glycemic State of A Patient”, whichdescribes a technique exploiting a combination of ECG signals andelectroencephalogram (EEG) for the detection of hypoglycemia.

See also U.S. Pat. No. 5,741,211 to Renirie, entitled “System And MethodFor Continuous Monitoring Of Diabetes-Related Blood Constituents.”According to Renirie, in a non-diabetic subject, a glucose load, asresults from food intake, leads to an increase in plasma glucose. Inturn, the pancreas produces an increase in blood insulin. Following anincrease in insulin, there is a cellular membrane change which resultsin infusion of potassium into the cells, and a subsequent decrease inblood potassium along with glucose uptake. The lowered extracellularpotassium, or blood potassium, shortens the cardiac monophasic actionpotential, and produces a steeper monophasic action potential upstroke.This in turn results in observable ECG changes, such as the developmentof U-waves, ST segment depression, and in particular a shortening of theT-wave amplitude and a small increase in the R wave. Renirie isprimarily directed to a Holter-type external monitor that analyzes theECG but has some speculative discussions pertaining to implantabledevices as well.

Although hyper/hypoglycemia detection techniques based on analysis ofthe ECG are somewhat helpful, there is a significant need to developIEGM-based techniques for detecting and distinguishing betweenhyperglycemia and hyperglycemia, as well as improved IEGM-basedtechniques for detecting cardiac ischemia.

These and other problems were solved by the invention of the parentapplication cited above. Briefly, using the techniques of the parentapplication (which are also described herein-below) hypoglycemia isdetected based on a change in ST segment elevation along with alengthening of either the interval between the QRS complex and the endof a T-wave (QTmax) or the interval between the QRS complex and the endof the T-wave (QTend). Hyperglycemia is detected based on a change in STsegment elevation along with minimal change in QTmax and in QTend.Ischemia is detected based on a shortening QTmax, alone or incombination with a change in ST segment elevation. Alternatively,cardiac ischemia is detected based on a change in ST segment elevationcombined with minimal change in QTend. By exploiting QTmax and QTend incombination with ST segment elevation, changes in ST segment elevationcaused by hypo/hyperglycemia can be properly distinguished from oneanother and from changes caused by ischemia.

The following table summarizes changes in the ST segment, QTmax andQTend in response to hypoglycemia, hyperglycemia and cardiac ischemiathat are exploited by the technique of the parent application. TABLE IST Segment QTmax QTend Hypoglycemia Significant Lengthens Lengthensdeviation Hyperglycemia Significant Little or no Little or no deviationchange change Ischemia Significant Shortens Little or no deviationchange Normal No significant No significant No significant deviationdeviation deviation

Another useful technique is set forth in U.S. Patent Application SerialNumber 2004/0077962 of Kroll, published Apr. 22, 2004, entitled “Systemand Method for Monitoring Blood Glucose Levels Using an ImplantableMedical Device.” The technique of Kroll is directed to detecting bloodglucose levels based on IEGM signals sensed by an implantable medicaldevice. Briefly, blood glucose levels are determined by an implantabledevice based on IEGM signals by detecting and examine a combination ofT-wave amplitude fraction and QTc interval. The technique may also beused to detect hypoglycemia based on changes in blood glucose levels.

Yet another useful technique is set forth in U.S. patent applicationSer. No. __/______ of Bharmi, filed Apr. 27, 2005, entitled “System andMethod for Detecting Hypoglycemia Based on a Paced DepolarizationIntegral Using an Implantable Medical Device,” (Attorney Docket No.A05P1032), which is assigned to the assignee of the present inventionand is incorporated by reference herein. Briefly, techniques areprovided therein specifically for detecting and tracking hypoglycemia.In one example, an implantable medical system tracks changes in a paceddepolarization integral (PDI). A significant increase in PDI over arelatively short period of time indicates the onset of hypoglycemia.Upon detection of hypoglycemia, appropriate warning signals aregenerated to alert the patient. Certain therapies automatically providedby the implantable system may also be controlled in response tohypoglycemia. For example, if the patient is an insulin-dependentdiabetic and the implantable system is equipped with an insulin pumpcapable of delivering insulin directly into the bloodstream, insulindelivery is automatically suspended until blood glucose levels return toacceptable levels. If the system includes an ICD, the ICD may becontrolled to begin charging defibrillation capacitors upon detection ofhypoglycemia so as to permit prompt delivery of a defibrillation shock,which may be needed if hypoglycemia triggers ventricular fibrillation.

Although the techniques described by Kroll and Bharmi as well as thetechniques of the parent application are effective for detecting anddistinguishing hypoglycemia and hyperglycemia, it would nevertheless bedesirable to provide further improvements so as to provide improveddetection specificity. By providing improved specificity in detectinghypoglycemia and hyperglycemia, any warning signals and any therapydelivered in response to hyper/hypoglycemia can be more reliablydelivered. Furthermore, cardiac ischemia detection techniques of thetype originally set forth in the parent application, which distinguishcardiac ischemia from hyper/hypoglycemia based on features of the IEGM,can also be more reliably performed. It is to this end that theinvention of the present patent application is primarily directed.Moreover, still other aspects of the invention are directed to providingtechniques for tracking changes in glycemic state so as to allowpatients to achieve improved glycemic control. In particular, it isdesirable to provide techniques for trending and trackinghyper/hypoglycemia in an effort to predict the onset of an episode ofhypoglycemia in advance so as to warn the patient and still otheraspects of the invention are directed to that end.

SUMMARY

In accordance with one illustrative embodiment, techniques are providedfor use with an implantable medical device for distinguishing betweenhypoglycemia and hyperglycemia based on internal electrical cardiacsignals (e.g. IEGMs). Briefly, an amplitude-based parameterrepresentative of amplitudes of selected electrical events sensed withinthe heart of the patient is detected, and then hypoglycemia andhyperglycemia are distinguished from one another based on theamplitude-based parameter.

In one example, the selected electrical events include one or more of:atrial depolarization events (i.e. P-waves of the IEGM); ventriculardepolarization events (i.e. QRS complexes of the IEGM); and ventricularrepolarization events (i.e. T-waves of the IEGM). The amplitude-basedparameter is representative of one or more of: the absolute values ofthe amplitudes of the selected electrical events; rates of change in theamplitudes of the selected electrical events over time; or beat by beatchanges in the amplitudes of the selected electrical events.

Insofar as atrial depolarization events are concerned (i.e. P-waves ofthe IEGM), in the example, the implantable device associates the onsetof hyperglycemia with a significant increase in the absolute value ofthe amplitudes of the atrial depolarization events, a significant rateof change in the amplitudes of the atrial depolarization events overtime, and a significant beat to beat change in the amplitudes of theatrial depolarization events. Hypoglycemia is instead exhibits a lack ofsignificant increase in the absolute value of the amplitudes of theatrial depolarization events, a lack of significant rate of change inthe amplitudes of the atrial depolarization events over time, and a lackof significant beat to beat change in the amplitudes of the atrialdepolarization events.

Insofar as ventricular repolarization events are concerned (i.e. T-wavesof the IEGM), in the example, the implantable device associates theonset of hypoglycemia with a significant increase in the absolute valueof the amplitudes of the ventricular repolarization events, asignificant rate of change in the amplitudes of the ventricularrepolarization events over time, and a significant beat to beat changein the amplitudes of the ventricular repolarization events.Hyperglycemia instead exhibits a lack of significant increase in theabsolute value of the amplitudes of the ventricular repolarizationevents, a lack of significant rate of change in the amplitudes of theventricular repolarization events over time, and a lack of significantbeat to beat change in the amplitudes of the ventricular repolarizationevents.

Thus, the changes manifest in P-waves due to hyperglycemia andhypoglycemia are essentially reversed in T-waves. In other words,whereas the onset of hyperglycemia triggers a significant and rapidincrease in P-wave amplitude, it is hypoglycemia that instead triggers asignificant and rapid increase in T-wave amplitude. Conversely, whereashypoglycemia yields no significant increase in P-wave amplitude, it ishyperglycemia that yields no significant increase in T-wave amplitude.Hence, a comparative analysis of P-wave and T-wave amplitudes observedwithin the IEGM is particularly useful for distinguishing hyperglycemiafrom hypoglycemia.

Insofar as ventricular depolarization events are concerned (i.e. QRScomplexes of the IEGM), in the example, the implantable deviceassociates the onset of hyperglycemia with: a greater increase in theabsolute value of the amplitudes of the ventricular depolarizationevents than occurring with hypoglycemia; a greater rate of change in theamplitudes of the ventricular depolarization events over time thanoccurring with hypoglycemia; and a greater beat to beat change in theamplitudes of the ventricular depolarization events than occurring withhypoglycemia. Thus, although both hyperglycemia and hypoglycemiamanifest an increase in the amplitude of the QRS complex, the increaseis both greater and more rapid during the onset of hyperglycemia thanduring the onset of hypoglycemia. Hence, an analysis of the amplitude ofQRS-complex is also helpful for distinguishing hyperglycemia fromhypoglycemia.

The following table summarizes changes in the atrial depolarization,ventricular depolarization and ventricular repolarization amplitudes inresponse to hypoglycemia and hyperglycemia that are exploited by theinvention. TABLE II HYPERGLYCEMIA HYPOGLYCEMIA Atrial Depolarization:Significant increase No significant Amplitude change AtrialDepolarization: Rapid increase No significant Rate of Change of changeAmplitude (with Time or Beat by Beat) Ventricular Depolarization:Significant increase Moderate significant Amplitude increase VentricularDepolarization: Rapid increase Less rapid increase Rate of Change ofAmplitude (with Time or Beat by Beat) Ventricular Repolarization: Nosignificant Significant increase Amplitude change VentricularRepolarization: No significant Rapid increase Rate of Change of changeAmplitude (with Time or Beat by Beat)

Analysis of changes in the ST segment, QTmax and/or QTend canadditionally be used to help distinguish hypoglycemia fromhyperglycemia.

In accordance with another aspect of the invention, techniques areprovided for directly detecting hyperglycemia based on selectedamplitude-based parameters or for directly detecting hypoglycemia basedon selected amplitude-based parameters. In one example, hyperglycemia isdetected by: detecting a depolarization amplitude-based parameterrepresentative of amplitudes of selected electrical depolarizationevents sensed within the heart of the patient; detecting arepolarization amplitude-based parameter representative of amplitudes ofelectrical repolarization events sensed within the heart of the patient;and then detecting hyperglycemia based on a significant increase in thedepolarization amplitude-based parameter combined with a lack ofsignificant change in the repolarization amplitude-based parameter. Thedepolarization amplitude-based parameter may be based on one or more of:atrial depolarization events and ventricular depolarization events.Hypoglycemia is detected by: detecting an atrial depolarizationamplitude-based parameter representative of amplitudes of electricalatrial depolarization events sensed within the heart of the patient;detecting a repolarization amplitude-based parameter representative ofamplitudes of electrical ventricular repolarization events sensed withinthe heart of the patient; and then detecting hypoglycemia based on asignificant increase in the repolarization amplitude-based parameter incombination with lack of significant change in the atrial depolarizationamplitude-based parameter.

Upon detecting and distinguishing hypoglycemia and/or hyperglycemia,appropriate warning signals are generated, which may include perceptiblesignals applied to subcutaneous tissue or short range telemetry warningsignals transmitted to a device external to the patient, such as abedside monitor. In one example, once a subcutaneous warning signal isperceived, the patient positions an external warning device above his orher chest. The handheld device receives the short-range telemetrysignals and provides audible or visual verification of the warningsignal. The handheld warning device thereby provides confirmation of thewarning to the patient, who may be otherwise uncertain as to the reasonfor the internally generated warning signal. Upon confirmation of thewarning, the patient then takes appropriate actions, such as ingestingfoods suitable for increasing blood glucose levels in response tohypoglycemia or taking additional insulin in response to hyperglycemia.

Certain therapies automatically provided by the implantable device mayalso be initiated or modified in response to hypoglycemia orhyperglycemia. If the patient is an insulin-dependent diabetic and theimplantable device is equipped with a drug pump capable of deliveringinsulin directly into the bloodstream, insulin delivery by the pump isautomatically suspended during hypoglycemia until blood glucose levelsreturn to acceptable levels. Insulin delivery is automatically increasedduring hyperglycemia, again until blood glucose levels return toacceptable levels. If the patient suffers hyperinsulanism and if thedrug pump is equipped to deliver medications appropriate tohyperinsulinism, delivery of such medications is titrated in response tothe glycemic state. In addition, if the device is an ICD, it may becontrolled to begin charging defibrillation capacitors upon detection ofhypoglycemia so as to permit prompt delivery of a defibrillation shock,which may be needed if hypoglycemia triggers VF due to a prolongation ofthe QT intervals. Additionally, or in the alternative, datarepresentative of episodes of hyper/hypoglycemia or trend informationpertaining to the amplitude-based parameters used to detect the episodesare stored for subsequent physician review, such as date/time andduration of the episode, the individual amplitude values detected, andany therapies automatically delivered. Trend information allows thepatient and physician to develop and implement strategies for achievingbetter glycemic control within the patient.

Also, preferably, the recorded information is used to predict episodesof hyper/hypoglycemia so that warning signals may be generated to alertthe patient to take appropriate action to prevent the episode fromoccurring. In one example, the prediction is performed by identifying atrend in increasing atrial depolarization amplitude. For example, if therecorded data indicates that the patient frequently has episodes ofhyperglycemia early in the morning and atrial depolarization amplitudelevels are found to be significantly increasing early on a particularmorning, then a warning signal is issued notifying the patient that anepisode of hyperglycemia is likely.

Hence, improved techniques are provided for reliably predicting,detecting and distinguishing hypoglycemia and hyperglycemia. Thetechniques are preferably performed by the implanted medical deviceitself so as to provide prompt warnings, if needed. Alternatively, thetechniques may be performed by external devices, such as bedsidemonitors or the like, based on IEGM signals detected by an implanteddevice then transmitted to the external device. Other detectiontechniques, such as PDI-based techniques or QT interval-based techniquesmay be exploited in combination with the techniques of the invention toenhance detection specificity.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the invention may be more readilyunderstood by reference to the following description taken inconjunction with the accompanying drawings, in which:

FIG. 1 is a simplified diagram illustrating an implantable stimulationdevice with at least three leads implanted in the heart of a patient fordelivering multi-chamber stimulation and shock therapy;

FIG. 2 is a functional block diagram of the implantable cardiacstimulation device of FIG. 1 illustrating basic elements of thestimulation device, and particularly illustrating components fordetecting cardiac ischemia, hypoglycemia, and hyperglycemia based onvarious combinations of QTmax, QTend and STdeviation and othercomponents for detecting and distinguishing hypoglycemia fromhyperglycemia based on amplitudes of selected electrical events;

FIG. 3 is a flow chart providing an overview of an exemplary methodperformed by the device of FIG. 2 for detecting cardiac ischemia basedon a reduction in QTmax;

FIG. 4 is a graph providing a stylized representation of the IEGM of asingle heartbeat, particularly illustrating the QTmax interval;

FIG. 5 is a graph providing exemplary representations of the IEGM of asingle heart beat, particularly illustrating a reduction in the QTmaxinterval caused by cardiac ischemia;

FIG. 6 is a flow chart providing an overview of an exemplary methodperformed by the device of FIG. 2 for detecting cardiac ischemia basedprimarily on a significant deviation in the ST segment along with littleor no change in the QTend interval;

FIG. 7 is a graph providing a stylized representation of the IEGM of asingle heartbeat, particularly illustrating STdeviation and the QTendinterval;

FIG. 8 is a graph providing exemplary representations of the IEGM of asingle heart beat, particularly illustrating a significant deviation inthe ST segment caused by cardiac ischemia, along with a lack of changein QTend;

FIG. 9 is a flow chart providing an overview of an exemplary methodperformed by a hypoglycemia detection system of FIG. 2 for detectinghypoglycemia based primarily on a significant lengthening of eitherQTmax or QTend;

FIG. 10 is a graph providing exemplary representations of the IEGM of asingle heartbeat, particularly illustrating a significant lengthening ofboth QTmax and QTend;

FIG. 11 is a flow chart providing an overview of an exemplary methodperformed by a hyperglycemia detection system of FIG. 2 for detectinghyperglycemia based primarily on a significant deviation in the STsegment along with little or no change in QTmax;

FIG. 12 is a graph providing exemplary representations of the IEGM of asingle heart beat, particularly illustrating a significant deviation inST segment caused by hyperglycemia, along with little or no change inQTmax;

FIG. 13 is a flow chart providing an overview of an exemplary methodperformed by the implantable device of FIG. 2 for distinguishing amongcardiac ischemia, hypoglycemia and hyperglycemia based on ST segment,QTmax, and QTend;

FIG. 14 is a flow chart providing an overview of an exemplary methodperformed by the implantable device of FIG. 2 for distinguishing amongcardiac ischemia, hypoglycemia and hyperglycemia based on ST segmentelevation and QTmax;

FIG. 15 is a flow chart providing an overview of an exemplary methodperformed by the implantable device of FIG. 2 for distinguishing amongcardiac ischemia, hypoglycemia and hyperglycemia based on ST segmentelevation and QTend;

FIG. 16 is a flow chart providing an overview of an exemplary methodperformed by the implantable device of FIG. 2 for detecting anddistinguishing hypoglycemia from hyperglycemia based on amplitudes ofselected electrical events;

FIG. 17 is a graph providing a stylized representation of the IEGM of asingle heartbeat, particularly illustrating P-wave, QRS-complex andT-wave amplitudes;

FIG. 18 is a flow chart providing an overview of an exemplary methodperformed by the implantable device of FIG. 2 for detecting anddistinguishing hypoglycemia and hyperglycemia based on based on P-wave,QRS-complex and T-wave amplitudes;

FIG. 19 is a graph illustrating changes in blood glucose levelsassociated with hyperglycemia and hypoglycemia;

FIG. 20 is a graph illustrating changes in P-wave amplitude associatedwith hyperglycemia and hypoglycemia;

FIG. 21 is a graph illustrating changes in QRS-complex amplitudeassociated with hyperglycemia and hypoglycemia; and

FIG. 22 is a graph illustrating changes in T-wave amplitude associatedwith hyperglycemia and hypoglycemia.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following description includes the best mode presently contemplatedfor practicing the invention. The description is not to be taken in alimiting sense but is made merely for the purpose of describing thegeneral principles of the invention. The scope of the invention shouldbe ascertained with reference to the issued claims. In the descriptionof the invention that follows, like numerals or reference designatorswill be used to refer to like parts or elements throughout.

Overview of Implantable Device

As shown in FIG. 1, there is a stimulation device 10 in electricalcommunication with the heart 12 of a patient by way of three leads, 20,24 and 30, suitable for delivering multi-chamber stimulation and shocktherapy. To sense atrial cardiac signals and to provide right atrialchamber stimulation therapy, the stimulation device 10 is coupled to animplantable right atrial lead 20 having at least an atrial tip electrode22, which typically is implanted in the right atrial appendage and anatrial ring electrode 23. To sense left atrial and ventricular cardiacsignals and to provide left chamber pacing therapy, the stimulationdevice 10 is coupled to a “coronary sinus” lead 24 designed forplacement in the “coronary sinus region” via the coronary sinus or forpositioning a distal electrode adjacent to the left ventricle and/oradditional electrode(s) adjacent to the left atrium. As used herein, thephrase “coronary sinus region” refers to the vasculature of the leftventricle, including any portion of the coronary sinus, great cardiacvein, left marginal vein, left posterior ventricular vein, middlecardiac vein, and/or small cardiac vein or any other cardiac veinaccessible by the coronary sinus. Accordingly, an exemplary coronarysinus lead 24 is designed to receive atrial and ventricular cardiacsignals and to deliver left ventricular pacing therapy using at least aleft ventricular tip electrode 26, left atrial pacing therapy using atleast a left atrial ring electrode 27, and shocking therapy using atleast a left atrial coil electrode 28.

The stimulation device 10 is also shown in electrical communication withthe heart by way of an implantable right ventricular lead 30 having, inthis embodiment, a right ventricular tip electrode 32, a rightventricular ring electrode 34, a right ventricular (RV) coil electrode36, and an SVC coil electrode 38. Typically, the right ventricular lead30 is transvenously inserted into the heart so as to place the rightventricular tip electrode 32 in the right ventricular apex so that theRV coil electrode is positioned in the right ventricle and the SVC coilelectrode 38 is positioned in the superior vena cava. Accordingly, theright ventricular lead 30 is capable of receiving cardiac signals, anddelivering stimulation in the form of pacing and shock therapy to theright ventricle. To provide a “tickle warning” signal, an additionalelectrode 31 is provided in proximity to the device can.

As illustrated in FIG. 2, a simplified block diagram is shown of themulti-chamber implantable stimulation device 10, which is capable oftreating both fast and slow arrhythmias with stimulation therapy,including cardioversion, defibrillation, and pacing stimulation. While aparticular multi-chamber device is shown, this is for illustrationpurposes only, and one of skill in the art could readily duplicate,eliminate or disable the appropriate circuitry in any desiredcombination to provide a device capable of treating the appropriatechamber(s) with cardioversion, defibrillation and pacing stimulation.

The housing 40 for the stimulation device 10, shown schematically inFIG. 2, is often referred to as the “can”, “case” or “case electrode”and may be programmably selected to act as the return electrode for all“unipolar” modes. The housing 40 may further be used as a returnelectrode alone or in combination with one or more of the coilelectrodes, 28, 36 and 38, for shocking purposes. The housing 40 furtherincludes a connector (not shown) having a plurality of terminals, 42,43, 44, 46, 48, 52, 54, 56 and 58 (shown schematically and, forconvenience, the names of the electrodes to which they are connected areshown next to the terminals). As such, to achieve right atrial sensingand pacing, the connector includes at least a right atrial tip terminal(A_(R) TIP) 42 adapted for connection to the atrial tip electrode 22 anda right atrial ring (A_(R) RING) electrode 43 adapted for connection toright atrial ring electrode 23. To achieve left chamber sensing, pacingand shocking, the connector includes at least a left ventricular tipterminal (V_(L) TIP) 44, a left atrial ring terminal (A_(L) RING) 46,and a left atrial shocking terminal (A_(L) COIL) 48, which are adaptedfor connection to the left ventricular ring electrode 26, the leftatrial tip electrode 27, and the left atrial coil electrode 28,respectively. To support right chamber sensing, pacing and shocking, theconnector further includes a right ventricular tip terminal (V_(R) TIP)52, a right ventricular ring terminal (V_(R) RING) 54, a rightventricular shocking terminal (R_(V) COIL) 56, and an SVC shockingterminal (SVC COIL) 58, which are adapted for connection to the rightventricular tip electrode 32, right ventricular ring electrode 34, theRV coil electrode 36, and the SVC coil electrode 38, respectively. Toprovide the “tickle warning” signal, an additional terminal 59 isprovided for connection to the tickle warning electrode 31 of FIG. 1.

At the core of the stimulation device 10 is a programmablemicrocontroller 60, which controls the various modes of stimulationtherapy. As is well known in the art, the microcontroller 60 (alsoreferred to herein as a control unit) typically includes amicroprocessor, or equivalent control circuitry, designed specificallyfor controlling the delivery of stimulation therapy and may furtherinclude RAM or ROM memory, logic and timing circuitry, state machinecircuitry, and I/O circuitry. Typically, the microcontroller 60 includesthe ability to process or monitor input signals (data) as controlled bya program code stored in a designated block of memory. The details ofthe design and operation of the microcontroller 60 are not critical tothe invention. Rather, any suitable microcontroller 60 may be used thatcarries out the functions described herein. The use ofmicroprocessor-based control circuits for performing timing and dataanalysis functions are well known in the art.

As shown in FIG. 2, an atrial pulse generator 70 and a ventricular pulsegenerator 72 generate pacing stimulation pulses for delivery by theright atrial lead 20, the right ventricular lead 30, and/or the coronarysinus lead 24 via an electrode configuration switch 74. It is understoodthat in order to provide stimulation therapy in each of the fourchambers of the heart, the atrial and ventricular pulse generators, 70and 72, may include dedicated, independent pulse generators, multiplexedpulse generators or shared pulse generators. The pulse generators, 70and 72, are controlled by the microcontroller 60 via appropriate controlsignals, 76 and 78, respectively, to trigger or inhibit the stimulationpulses.

The microcontroller 60 further includes timing control circuitry 79which is used to control the timing of such stimulation pulses (e.g.,pacing rate, atrio-ventricular (AV) delay, atrial interconduction (A-A)delay, or ventricular interconduction (V-V) delay, etc.) as well as tokeep track of the timing of refractory periods, blanking intervals,noise detection windows, evoked response windows, alert intervals,marker channel timing, etc., which is well known in the art. Switch 74includes a plurality of switches for connecting the desired electrodesto the appropriate I/O circuits, thereby providing complete electrodeprogrammability. Accordingly, the switch 74, in response to a controlsignal 80 from the microcontroller 60, determines the polarity of thestimulation pulses (e.g., unipolar, bipolar, combipolar, etc.) byselectively closing the appropriate combination of switches (not shown)as is known in the art.

Atrial sensing circuits 82 and ventricular sensing circuits 84 may alsobe selectively coupled to the right atrial lead 20, coronary sinus lead24, and the right ventricular lead 30, through the switch 74 fordetecting the presence of cardiac activity in each of the four chambersof the heart. Accordingly, the atrial (ATR. SENSE) and ventricular (VTR.SENSE) sensing circuits, 82 and 84, may include dedicated senseamplifiers, multiplexed amplifiers or shared amplifiers. The switch 74determines the “sensing polarity” of the cardiac signal by selectivelyclosing the appropriate switches, as is also known in the art. In thisway, the clinician may program the sensing polarity independent of thestimulation polarity. Each sensing circuit, 82 and 84, preferablyemploys one or more low power, precision amplifiers with programmablegain and/or automatic gain control, bandpass filtering, and a thresholddetection circuit, as known in the art, to selectively sense the cardiacsignal of interest. The automatic gain control enables the device 10 todeal effectively with the difficult problem of sensing the low amplitudesignal characteristics of atrial or ventricular fibrillation. Theoutputs of the atrial and ventricular sensing circuits, 82 and 84, areconnected to the microcontroller 60 which, in turn, are able to triggeror inhibit the atrial and ventricular pulse generators, 70 and 72,respectively, in a demand fashion in response to the absence or presenceof cardiac activity in the appropriate chambers of the heart.

For arrhythmia detection, the device 10 utilizes the atrial andventricular sensing circuits, 82 and 84, to sense cardiac signals todetermine whether a rhythm is physiologic or pathologic. As used herein“sensing” is reserved for the noting of an electrical signal, and“detection” is the processing of these sensed signals and noting thepresence of an arrhythmia. The timing intervals between sensed events(e.g., P-waves, R-waves, and depolarization signals associated withfibrillation which are sometimes referred to as “F-waves” or“Fib-waves”) are then classified by the microcontroller 60 by comparingthem to a predefined rate zone limit (i.e., bradycardia, normal, lowrate VT, high rate VT, and fibrillation rate zones) and various othercharacteristics (e.g., sudden onset, stability, physiologic sensors, andmorphology, etc.) in order to determine the type of remedial therapythat is needed (e.g., bradycardia pacing, antitachycardia pacing,cardioversion shocks or defibrillation shocks).

Cardiac signals are also applied to the inputs of an analog-to-digital(A/D) data acquisition system 90. The data acquisition system 90 isconfigured to acquire intracardiac electrogram signals, convert the rawanalog data into a digital signal, and store the digital signals forlater processing and/or telemetric transmission to an external device102. The data acquisition system 90 is coupled to the right atrial lead20, the coronary sinus lead 24, and the right ventricular lead 30through the switch 74 to sample cardiac signals across any pair ofdesired electrodes.

The microcontroller 60 is further coupled to a memory 94 by a suitabledata/address bus 96, wherein the programmable operating parameters usedby the microcontroller 60 are stored and modified, as required, in orderto customize the operation of the stimulation device 10 to suit theneeds of a particular patient. Such operating parameters define, forexample, pacing pulse amplitude or magnitude, pulse duration, electrodepolarity, rate, sensitivity, automatic features, arrhythmia detectioncriteria, and the amplitude, waveshape and vector of each shocking pulseto be delivered to the patient's heart 12 within each respective tier oftherapy. Other pacing parameters include base rate, rest rate andcircadian base rate.

Advantageously, the operating parameters of the implantable device 10may be non-invasively programmed into the memory 94 through a telemetrycircuit 100 in telemetric communication with the external device 102,such as a programmer, transtelephonic transceiver or a diagnostic systemanalyzer. The telemetry circuit 100 is activated by the microcontrollerby a control signal 106. The telemetry circuit 100 advantageously allowsintracardiac electrograms and status information relating to theoperation of the device 10 (as contained in the microcontroller 60 ormemory 94) to be sent to the external device 102 through an establishedcommunication link 104. In the preferred embodiment, the stimulationdevice 10 further includes a physiologic sensor 108, commonly referredto as a “rate-responsive” sensor because it is typically used to adjustpacing stimulation rate according to the exercise state of the patient.However, the physiological sensor 108 may further be used to detectchanges in cardiac output, changes in the physiological condition of theheart, or diurnal changes in activity (e.g., detecting sleep and wakestates). Accordingly, the microcontroller 60 responds by adjusting thevarious pacing parameters (such as rate, AV Delay, V-V Delay, etc.) atwhich the atrial and ventricular pulse generators, 70 and 72, generatestimulation pulses. While shown as being included within the stimulationdevice 10, it is to be understood that the physiologic sensor 108 mayalso be external to the stimulation device 10, yet still be implantedwithin or carried by the patient.

The stimulation device additionally includes a battery 110, whichprovides operating power to all of the circuits shown in FIG. 2. For thestimulation device 10, which employs shocking therapy, the battery 110must be capable of operating at low current drains for long periods oftime, and then be capable of providing high-current pulses (forcapacitor charging) when the patient requires a shock pulse. The battery110 must also have a predictable discharge characteristic so thatelective replacement time can be detected. Accordingly, the device 10preferably employs lithium/silver vanadium oxide batteries, as is truefor most (if not all) current devices. As further shown in FIG. 2, thedevice 10 is shown as having an impedance measuring circuit 112, whichis enabled by the microcontroller 60 via a control signal 114.

In the case where the stimulation device 10 is intended to operate as animplantable cardioverter/defibrillator (ICD) device, it detects theoccurrence of an arrhythmia and automatically applies an appropriateelectrical shock therapy to the heart aimed at terminating the detectedarrhythmia. To this end, the microcontroller 60 further controls ashocking circuit 116 by way of a control signal 118. The shockingcircuit 116 generates shocking pulses of low (up to 0.5 joules),moderate (0.5-10 joules), or high energy (11 to 40 joules), ascontrolled by the microcontroller 60. Such shocking pulses are appliedto the heart 12 through at least two shocking electrodes, and as shownin this embodiment, selected from the left atrial coil electrode 28, theRV coil electrode 36, and/or the SVC coil electrode 38. As noted above,the housing 40 may act as an active electrode in combination with the RVelectrode 36, or as part of a split electrical vector using the SVC coilelectrode 38 or the left atrial coil electrode 28 (i.e., using the RVelectrode as a common electrode). Cardioversion shocks are generallyconsidered to be of low to moderate energy level (so as to minimize painfelt by the patient), and/or synchronized with an R-wave and/orpertaining to the treatment of tachycardia. Defibrillation shocks aregenerally of moderate to high energy level (i.e., corresponding tothresholds in the range of 5-40 joules), delivered asynchronously (sinceR-waves may be too disorganized), and pertaining exclusively to thetreatment of fibrillation. Accordingly, the microcontroller 60 iscapable of controlling the synchronous or asynchronous delivery of theshocking pulses.

In addition, the stimulation device may be configured to performAutomatic Mode Switching (AMS) wherein the pacemaker reverts from atracking mode such as a VDD or DDD mode to a nontracking mode such asVVI or DDI mode. VDD, DDD, VVI and DDI are standard device codes thatidentify the mode of operation of the device. DDD indicates a devicethat senses and paces in both the atria and the ventricles and iscapable of both triggering and inhibiting functions based upon eventssensed in the atria and the ventricles. VDD indicates a device thatsensed in both the atria and ventricles but only paces in theventricles. A sensed event on the atrial channel triggers ventricularoutputs after a programmable delay, the pacemaker's equivalent of a PRinterval. VVI indicates that the device is capable of pacing and sensingonly in the ventricles and is only capable of inhibiting the functionsbased upon events sensed in the ventricles. DDI is identical to DDDexcept that the device is only capable of inhibiting functions basedupon sensed events, rather than triggering functions. As such, the DDImode is a non-tracking mode precluding its triggering ventricularoutputs in response to sensed atrial events. Numerous other device modesof operation are possible, each represented by standard abbreviations ofthis type.

Further, with regard to FIG. 2, microcontroller 60 includes: a cardiacischemia detection unit 101 for controlling the detection of episodes ofcardiac ischemia; hypoglycemia detection unit 103 for controlling thedetection of episodes of hypoglycemia; and a hyperglycemia detectionunit 105 for controlling the detection of episodes of hyperglycemia. Awarning unit 107 controls delivery of warning signals to the patientindicative of ischemia, hypoglycemia, or hyperglycemia. In particular,warning unit 107 controls a tickle circuit 109 that generatessubcutaneous perceptible warning signals via lead 31 (FIG. 1), which isconnected via connector 111. Device case electrodes 40 may be used asthe return electrode for the tickle warning signal. Thereafter, warningunit 107 controls a short-range telemetry system 113 to transmit warningsignals to an external handheld warning device 115 for confirmation.Additionally, a therapy control unit 117 may be provided to controltherapy based upon the detection of ischemia, hypoglycemia orhyperglycemia. If an implantable drug 119 is provided, such as aninsulin pump, the therapy control unit also controls delivery of insulinor other medications using the drug pump. The operation of components101-119 is described below primarily with reference to FIGS. 1-15.

The microcontroller additionally includes an amplitude-basedhypo/hyperglycemia unit 121 for predicting, detecting and/ordistinguishing hypoglycemia from hyperglycemia based on the amplitudesof P-waves, QRS-complexes and T-waves, which is described belowprimarily with reference to FIGS. 16-22. The results of analysisperformed by the hypo/hyperglycemia unit 121 may be exploited bydetection units 101-105 to improve the specificity by whichhypoglycemia, hyperglycemia and cardiac ischemia are detected, or theanalysis may be exploited for any other advantageous purpose.

Referring now to the remaining figures, flow charts, graphs and otherdiagrams illustrate the operation and novel features of stimulationdevice 10 as configured in accordance with exemplary embodiments of theinvention. In the flow charts, the various algorithmic steps aresummarized in individual “blocks”. Such blocks describe specific actionsor decisions made or carried out as the algorithm proceeds. Where amicrocontroller (or equivalent) is employed, the flow charts provide thebasis for a “control program” that may be used by such a microcontroller(or equivalent) to effectuate the desired control of the stimulationdevice. Those skilled in the art may readily write such a controlprogram based on the flow charts and other descriptions presentedherein.

Cardiac Ischemia Detection Based on QTmax

FIG. 3 provides an overview of a QTmax-based cardiac ischemia detectiontechnique performed by the device of FIG. 2. Initially, at step 200,IEGM signals are received and QRS-complexes and T-waves are identifiedtherein. Then, the interval from the beginning of the QRS complex to thepeak or maximum absolute amplitude of the T-wave is calculated, at step202. This interval is referred to herein as QTmax. The Q wave of the QRScomplex may be identified as the point within the QRS complex where theIEGM signal exceeds a threshold value set based on the maximum amplitudeof the QRS complex itself. The maximum of the T-wave may be identifiedas the maximum point within a T-wave interval beginning 250 ms followingthe Q wave of the QRS complex and extending for 200 ms. These are merelyexemplary values. At step 204, the onset of a cardiac ischemia isdetected based upon detection of a significant shortening of QTmax.Routine experimentation may be performed to determine what constitutes“significant” insofar as changes in QTmax are concerned (and insofar asany other changes referred to herein as being significant areconcerned.) In one example, a 10% or greater change in a given parameteris deemed to be significant. Note that QTmax values may be derived fromeither paced or sensed events but values derived from paced and sensedevents should not be combined. In addition, QTmax varies with heart rateand so should be normalized based on heart rate. Bazettte's equation maybe used for normalizing QTmax (and for normalizing other parametersdiscussed herein.) Additionally, or in the alternative, at step 204, thedevice calculates an “ischemic burden” based on QTmax, which isrepresentative of the proportion of the time ischemia is detected. Inone example, the ischemic burden is a numerical value representative ofthe extent to and/or the time during which QTmax is shorter than itsrunning average. Steps 200-204 are preferably performed once every 30seconds.

So long as no ischemia is detected, steps 200-204 are merely repeated.If ischemia is detected, however, the patient is warned of the ischemiaby application of an internal perceptible “tickle” notification signal,at step 206. If the device is configured to generate warning signals forother conditions, such as hyperglycemia or hypoglycemia, the devicepreferably employs different notification signal frequencies for thedifferent warnings so that the patient can properly distinguish betweendifferent warnings. In addition, warning signals may be transmittedusing a short-range telemetry system to a handheld warning device usingtechniques described within the above-referenced patent application toWang et al. The handheld warning device thereby provides confirmation ofthe warning to the patient, who may be otherwise uncertain as to thereason for the internally generated tickle warning signal. Additionally,if so equipped, the device may automatically control therapy in responseto the ischemia. For example, if a drug pump is implanted within thepatient, the pump may be controlled to deliver suitableanti-thrombolytic medications directly to the patient. Implantabledevices for delivering anti-thrombolytic drugs are discussed in U.S.Pat. No. 5,960,797 to Kramer, et al. The device may also change pacingparameters in response to the detection of ischemia to, for example,deactivate overdrive pacing, which may exacerbate the ischemia. Otherforms of elevated pacing may be discontinued as well, such as AFsuppression therapy or activity-based rate responsive pacing. Varioustechniques for controlling delivery of therapy in response to ischemiaare discussed U.S. Pat. No. 6,256,538 to Ekwall, listed above. See alsoU.S. Pat. No. 6,377,852 to Bornzin et al., which provides techniques forslowing the heart rate in response to ischemia. In addition, if thedevice is an ICD, then it may be controlled to immediately begincharging defibrillation capacitors in expectation of delivery of adefibrillation shock, which may be needed if the ischemia triggers VF.

Hence, FIG. 3 provides an overview of technique that seeks to detect theonset of cardiac ischemia based primarily on changes in QTmax. As willbe explained below, additional parameters of the IEGM signal, such asSTdeviation, may be employed to confirm the detection made based upon toQTmax. Insofar as the detection of T-waves at step 200 is concerned, theinvention may exploit techniques set forth in the aforementioned PatentApplication of Kroll (Serial Number 2004/0077962). Certain techniquesdescribed therein are particularly well suited for detecting T-waveswith a high degree of accuracy to permit precise detection of featuresof the T-wave (such as its peak) so as to achieve more precisemeasurement of QRS/T-wave intervals. The patent application to Kroll isfully incorporated by reference herein. The invention also may exploitT-wave detection techniques set forth within the aforementioned patentapplication to Min et al., which help prevent P-waves from beingmisinterpreted as T-waves on unipolar sensing channels.

FIG. 4 illustrates the QTmax interval. Briefly, the figure provides astylized representation of an exemplary IEGM trace 208 for a singleheartbeat for a patient suffering myocardial ischemia. The stylizedrepresentation of the IEGM signal of FIG. 4 is provided for illustrativepurposes and should not be construed as an actual, clinically detectedIEGM signal. The heartbeat includes a P-wave 210 representative of anatrial depolarization, a QRS complex 212 representative of a ventriculardepolarization and a T-wave 214 representative of ventricularrepolarization. The QRS complex itself is defined by points Q, R, and S.Q represents the beginning of the complex; R represents the peak of thecomplex; and S represents the end of the complex. In the examplesdescribed and illustrated herein, the aforementioned QTmax interval isspecified as the time interval from point Q to the peak or maximumamplitude point of T-wave. However, QTmax may alternatively becalculated based on other points or features of the QRS complex, such asthe R point or the S point of the complex, so long as the calculationsare consistent. As it is used herein, the “Q” of QTmax generally refersto the QRS complex and not specifically to the Q point of the QRScomplex. Hence, the term QTmax encompasses RTmax as one example andSTmax as another example. Also, in the particular example of FIG. 4, thepeak of the T-wave is positive, i.e. it is greater than a baselinevoltage of the IEGM signal. This need not be the case. In otherexamples, the peak has a negative value with respect to a baseline ofthe IEGM signal. The polarity of the entire signal may also be reversed.Herein, the peak or maximum amplitude of T-wave refers to the peak ormaximum of the absolute value of the difference between the T-wavevoltage and the baseline voltage of the IEGM signal. The baselinevoltage 216 may be measured during an interval prior to the P-wave, asshown. The interval may be, for example, 50 milliseconds (ms) induration, beginning 100 ms prior to the P-wave. Alternatively, theinterval may be timed relative to the QRS complex. If timed relative tothe QRS complex, the interval may commence 250 ms prior to the R wave ofthe QRS complex. Also alternatively, a single detection point may beused, rather than a detection interval.

FIG. 5 illustrates change in QTmax brought on by acute myocardialischemia. A first exemplary IEGM trace 218 represents a heartbeat ofhealthy patient, i.e. one not subject to cardiac ischemia, hypoglycemiaor hyperglycemia. A second trace 220 illustrates the heartbeat for apatient suffering an acute myocardial ischemia. The traces are IEGMsignals derived from voltage differences between the tip of a rightventricular (RV) lead and the device case. Note first that the IEGMtrace for the healthy patient exhibits a T-wave that is reversed inpolarity with respect to T-wave of the patient suffering the ischemia.T-wave inversion is typical during ischemia as well as during otherconditions such as electrolyte abnormalities, which influencerepolarization. Therefore, FIG. 5 illustrates that the QTmax feature isvalid even in the presence of a T-wave inversion. In any case, for thepurposes of ischemia detection, the peak of the T-wave during ischemiaoccurs earlier than the corresponding peak without ischemia. In otherwords, QTmax during ischemia 222 is shorter than QTmax without ischemia224. Hence, a large positive value of ΔQTmax (226) is observed, whereΔQTmax represents the amount of the reduction in QTmax. A negative valueof ΔQTmax is associated with an increase in interval length. In theexample FIG. 5, ΔQTmax is represented as a positive number. Note thatsignificant negative ΔQTmax intervals may also be observed which, aswill be explained below, are instead indicative of hypoglycemia.

ΔQTmax is the value used to detect the onset of ischemia. Preferably,any change in QTmax from a current baseline value is tracked. In oneexample, the device tracks a running average of QTmax intervals (derivedfrom sensed events and normalized based on heart rate) for use as abaseline value. Different baseline values may be calculated fordifferent heart rate-ranges. In any case, for each new heartbeat, thedevice compares the QTmax interval for that heartbeat against theappropriate baseline to calculate ΔQTmax for that heartbeat. ΔQTmaxvalues are averaged over, e.g., eight to sixteen heartbeats and thencompared against a predetermined QTmax-based threshold. If the averageexceeds the threshold, cardiac ischemia is thereby indicated. Thethreshold is a programmable value set, for example, based upon apercentage of the running average of the QTmax interval. In one specificexample, if ΔQTmax is a positive value, which exceeds 10% of the runningaverage of the QTmax intervals, cardiac ischemia is thereby indicated(i.e. QTmax has been found to be reduced by 10%). Otherwise conventionalthreshold comparison techniques may be employed for use with ΔQTmax. Inanother example, rather than comparing an average based on eight tosixteen values to the threshold, the occurrence of only a single ΔQTmaxvalue exceeding the threshold is indicative of ischemia. In yet anotherexample, if ΔQTmax exceeds the threshold for three out of fiveheartbeats, ischemia is indicated. Multiple thresholds may be defined,if desired, to trigger warning signals indicative of different levels ofurgency. For example, if ΔQTmax exceeds a first, lower threshold, awarning signal indicative of a moderate ischemia is issued. If ΔQTmaxexceeds a higher threshold, a second warning signal indicative of a moreserious ischemia is issued. As can be appreciated, a wide variety ofspecific implementations maybe provided in accordance with the generaltechniques described herein. Routine experimentation may be performed todetermine appropriate threshold levels.

Hence, FIGS. 3-5 provide an overview of techniques for detecting theonset of cardiac ischemia based on changes in the QTmax interval. Aswill be explained below, particularly with reference to FIG. 13,STdeviation may be used to corroborate any cardiac ischemia detectionmade based upon QTmax intervals. Other parameters may be used as well tocorroborate the detection of cardiac ischemia, including postT-wave-based detection parameters described in the above-referencedpatent application to Wang et al. and T-wave energy-based parameters andT-wave slope-based parameters described in the above-referenced patentapplication Min et al.

Cardiac Ischemia Detection Based on STdeviation and QTend

FIG. 6 provides an overview of a QTend-based cardiac ischemia detectiontechnique performed by the device of FIG. 2. Many aspects of thetechnique are similar to those of the technique of FIG. 3 and will notbe described again in detail. Initially, at step 300, IEGM signals arereceived and QRS-complexes and T-waves are identified therein. Then, theinterval from the beginning of the QRS complex to the end of the T-waveis calculated, at step 302. This interval is referred to herein asQTend. In the examples described and illustrated herein, the QTendinterval is specified as the time interval from point Q of the QRScomplex to the end point of the T-wave. However, as with QTmax, QTendmay alternatively be calculated based on other points or features of theQRS complex, such as the R point or the S point of the complex, so longas the calculations are consistent. The elevation of the interval fromthe end of the QRS complex to the beginning of the T-wave is alsocalculated, at step 304. This interval is referred to herein as the STsegment, its elevation is referred to as the ST elevation, and changesin the ST elevation is the STdeviation. Otherwise conventionaltechniques for detecting ST segment elevation may be used. Detection ofST segment elevation is discussed, for example, in U.S. Pat. Nos.6,016,443 and 6,256,538 to Ekwall, listed above. At step 306, the onsetof a cardiac ischemia is detected based upon observation of asignificant deviation in the ST segment along with little or no changein QTend. A deviation in the ST is preferably calculated as a change inthe average amplitude of the ST segment. Since the polarity of the IEGMsignal is arbitrary, this may, in some cases, represent an increase involtage of the ST segment and in other cases a decrease in voltage. Itis the change in ST segment elevation that is important. As before, datafrom paced and sensed events should not be combined. QTend values shouldbe normalized based on heart rate. Moreover, ST segments may bereferenced beat-by-beat to either the PQ or TP regions of the IEGM.

Additionally, or in the alternative, at step 304, the device calculatesan ischemic burden based on STdeviation and QTend, which isrepresentative of the risk of ischemia. In one example, the ischemicburden is a single metric value derived from STdeviation and changes inQTend. Techniques for combining different parameters into a singlemetric value are set forth in U.S. Patent Application 2004/0138716, toKoh et al., entitled “System and Method for Detecting Circadian StatesUsing an Implantable Medical Device”, published Jul. 15, 2004. If QTendand STdeviation are measured for diagnostic purposes only, steps 300-306are preferably performed once an hour to calculated and record theischemic burden. If measured for detecting ischemia, steps 300-306 arepreferably performed more often, e.g. once every 30 seconds. In anycase, so long as no ischemia is detected, steps 300-306 are merelyrepeated. If ischemia is detected, however, the patient is warned of theischemia, at step 308, and, if so equipped, the device automaticallycontrols therapy in response to the ischemia. If the device is an ICD,it may be controlled to immediately begin charging defibrillationcapacitors.

Hence, FIG. 6 provides an overview of technique that seeks to detect theonset of cardiac ischemia based on a combination of STdeviation andQTend. Additional parameters of the IEGM signal, such as theaforementioned QTmax interval, may be employed to confirm the detection.FIG. 7 illustrates ST segment elevation and the QTend interval. Briefly,FIG. 7 provides a stylized representation of an exemplary IEGM trace 310for a single heartbeat for a patient suffering a myocardial ischemia.The ST segment 312 is the interval from the end of the QRS complex tothe start of the T-wave. The duration of this interval is not ofinterest in this technique. However, its deviation, i.e. the extent towhich its elevation changes over time is of interest. To calculate theelevation of an individual ST segment deviation, the device identifies awindow 316 with the ST segment. The elevation of the ST segment(relative to a baseline voltage) within the window is denoted byreference numeral 318. The ST segment elevation may be measured during aspecified interval following the QRS complex, as shown. The interval maybe, for example, 50 ms in duration, beginning 50 ms following the R waveof the QRS complex. For ventricular paced events, the interval maybegin, for example, 80 ms following a V-pulse and extend for 50 ms.These are merely exemplary values. The elevation may be quantified basedon the mean of the ST segment sample. Meanwhile, the QTend interval isthe time interval between the beginning of the QRS complex and the endpoint of the T-wave, i.e. the point at which the slope of the T-wavefollowing its peak becomes substantially flat. Techniques for detectingT-wave slope are set forth in the aforementioned patent application toMin et al. The QTend interval is denoted by reference numeral 321.

FIG. 8 illustrates changes in ST segment elevation brought on by acutemyocardial ischemia. A first exemplary IEGM trace 320 represents aheartbeat of a healthy patient, i.e. one not subject to cardiac ischemiaor hypo/hyperglycemia. A second trace 322 illustrates the heartbeat fora patient suffering an acute myocardial ischemia. As with other tracesillustrated herein, the IEGM signals of FIG. 8 are exemplaryrepresentations of IEGM signals provided for illustrative purposes only.Comparing the two traces, the elevation of the ST-segment duringischemia (323) is much greater than the elevation of the ST-segmentwithout ischemia (325), i.e. there is a significant STdeviation.However, there is little or no change in QTend, i.e. the absolute valueof ΔQTend is substantially zero, where ΔQTend represents the amount ofthe reduction, if any, in QTend interval duration. (A positive value ofΔQTmax is associated with a decrease in interval length. A negativevalue of ΔQTmax is associated with an increase in interval length. Forthe purposes of the technique of FIG. 6, only the magnitude of anychange in QTend is important.) Hence, QTend helps corroborate thedetection of ischemia made based on STdeviation. In particular, as willbe explained in more detail below with reference to FIGS. 9-10, a changein ST segment elevation brought on by hypoglycemia will additionallytrigger a significant increase in QTend. Hence, without an examinationof QTend, it may not be possible to reliably distinguish a change in STsegment elevation caused by ischemia from a change caused byhypoglycemia.

Preferably, any changes in the ST segment elevation and in QTend fromcurrent baseline values are tracked. In one example, the device tracks arunning average of the ST segment elevation (as derived from sensedevents) and then, for each new heartbeat, the device compares the STsegment elevation for that heartbeat against the running average tocalculate an STdeviation value for that heartbeat. Note that ST segmentvalues need not be normalized based on heart rate. The device alsotracks a running average of the QTend interval (as derived from sensedevents and normalized based on heart rate) and then, for each newheartbeat, compares the QTend interval for that heartbeat against therunning average to calculate a ΔQTend value for that heartbeat. Thevalue of STdeviation for the heartbeat is averaged over, e.g., eight tosixteen heartbeats and compared against a predetermined deviation-basedthreshold. If the average exceeds the threshold, then the absolute valueof ΔQTend is also averaged over eight to sixteen heartbeats and comparedagainst a predetermined ΔQTend-based threshold. If STdeviation exceedsits respective threshold (indicating a significant change in ST segmentelevation), but the absolute value of ΔQTend does not exceed itsrespective threshold (indicating little or no change in QTend), thencardiac ischemia is thereby indicated. (If STdeviation exceeds itsrespective threshold and the absolute value of ΔQTend also exceeds itsrespective threshold, an indication of hypoglycemia may instead beprovided. See FIG. 13, discussed below.)

The various thresholds are programmable values set, for example, basedupon respective running averages. In one specific example, the thresholdfor ΔQTend is set to 10% of the running average of the QTend intervals.The threshold for STdeviation may be set, for example, based on somepercentage (e.g. 20%) of a running average of peak-to-peak voltageswings in QRS complexes, i.e. based on a percentage of the averagedifference from a maximum positive voltage to a maximum negative voltagewithin each QRS complex. Alternatively, the threshold for STdeviationmay be set to a preset voltage difference, such as 0.25-0.5 milli-Volts(mV). As with the QTmax-based technique, alternative thresholdcomparison techniques may instead be used. Multiple thresholds may bedefined, in some implementations, to trigger warning signals indicativeof different levels of urgency. Routine experimentation may be performedto determine appropriate threshold levels.

Hence, FIGS. 6-8 provide an overview of techniques for detecting theonset of cardiac ischemia based on an examination of ST segmentdeviation in conjunction with QTend interval. Other parameters may beused to further corroborate the detection of cardiac ischemia, such asthe QTmax interval and parameters described in the above-referencedpatent applications to Wang et al. and Min et al. In the next section,techniques for detecting hypoglycemia will be described.

Hypoglycemia Detection Based on QTmax and/or QTend

FIG. 9 provides an overview of hypoglycemia detection techniquesperformed by the device of FIG. 2. Many aspects of this technique aresimilar to those of the ischemia detection techniques described aboveand will not be described again in detail. Initially, at step 400, IEGMsignals are received and QRS-complexes and T-waves are identifiedtherein. Then, at step 402, QTmax and QTend intervals are measured. Atstep 404, the onset of hypoglycemia is detected based upon observationof a significant lengthening of either QTend or QTmax or both. In thisregard, both QTmax and QTend increase due to hypoglycemia. Hence, one orthe other is sufficient to detect hypoglycemia. Both are preferred toenhance detection reliability. A change in ST segment elevation may beused to further corroborate the detection (see FIG. 13). As before, datafrom paced or sensed events should not be combined. QTmax and QTendintervals should be normalized based on heart rate.

Additionally, or in the alternative, STdeviation, QTmax and QTend may bestored for diagnostic purposes. The device may calculate a single valuerepresentative of the risk of hypoglycemia based on a combination ofSTdeviation, QTmax and QTend, similar to the ischemic burden discussedabove. In any case, so long as hypoglycemia is not detected, steps400-404 are merely repeated. If hypoglycemia is detected, however, thepatient is warned, at step 406. Preferably, the warning signal differsfrom the one generated for ischemia. If so equipped, the device mayautomatically initiate therapy appropriate for responding tohypoglycemia. For example, if an insulin pump is implanted within adiabetic patient, the pump may be controlled to adjust the dosage ofinsulin in response to hypoglycemia. Techniques for controlling deliveryof therapy in response to hypoglycemia are set forth in the PatentApplication of Kroll, incorporated by reference above. Informationregarding implantable insulin pumps may be found in U.S. Pat. No.4,731,051 to Fischell and in U.S. Pat. No. 4,947,845 to Davis. Hence,FIG. 9 provides an overview of technique that seeks to detect the onsetof hypoglycemia based on a lengthening of QTmax or QTend. FIG. 10illustrates QTmax and QTend brought on by hypoglycemia, as well aschanges in ST segment elevation. A first exemplary IEGM trace 410represents a heartbeat of a healthy patient, i.e. one not subject tohypo/hyperglycemia or cardiac ischemia. A second trace 412 illustratesthe heartbeat for a patient suffering from hypoglycemia. As with othertraces illustrated herein, the IEGM signals of FIG. 10 are exemplaryrepresentations of IEGM signals provided for illustrative purposes only.Comparing the two traces, there is a significant lengthening of bothQTmax and QTend, i.e. both ΔQTmax and ΔQTend are large in magnitude. (Asexplained above, ΔQTmax and ΔQTend are defined as positive numbers for areduction in interval length and as negative numbers for an increase ininterval length.)

Hence, an increase in either QTmax or QTend or both allows the device todetect hypoglycemia. STdeviation may be used to corroborate thedetermination. As can be seen from FIG. 10, the elevation of the STsegment changes in response to hypoglycemia. Preferably, any changes inQTmax and/or QTend are measured with respect to baseline values of thoseparameters. In one example, the device tracks running averages QTmax andQTend (as derived from sensed events and normalized based on heart rate)fro use as baseline values. Different baseline values may be calculatedfor different heart rate ranges. Then for each new heartbeat, the devicecompares new values for those parameters against the appropriatebaseline values to calculate ΔQTmax and ΔQTend values for thatheartbeat. In the example, the ΔQTmax and ΔQTend values are averagedover eight to sixteen heartbeats. ΔQTmax is compared against apredetermined ΔQTmax-based threshold and ΔQTend is compared against apredetermined ΔQTend-based threshold and. These thresholds may differ invalue from the corresponding thresholds discussed above. If ΔQTmax andΔQTend both exceed their respective thresholds, an indication ofhypoglycemia is thereby provided. The various thresholds areprogrammable values set, for example, based upon percentages of runningaverages of the respective interval. Again, multiple thresholds may bedefined, if desired, to trigger warning signals indicative of differentlevels of urgency. Routine experimentation may be performed to determineappropriate threshold levels. In the next section, techniques forinstead detecting hyperglycemia will be described.

Hyperglycemia Detection based on STdeviation, QTmax and QTend

FIG. 11 provides an overview of hyperglycemia detection techniquesperformed by the device of FIG. 2. Many aspects of this technique aresimilar to those of the detection techniques described above and willnot be described again in detail. Initially, at step 500, IEGM signalsare received and QRS-complexes and T-waves are identified therein. Then,at step 502, QTmax intervals are measured and, at step 504, ST segmentelevation is detected. At step 506, the onset of a hyperglycemia isdetected based upon detection of a significant change in ST segmentelevation along with little or no change in QTmax. A change in STsegment elevation along with a shortening of QTmax is instead indicativeof cardiac ischemia. Note that, with hyperglycemia, neither QTmax norQTend changes significantly. However, a change in ST segment elevationalong with little or no change in QTend may also be indicative of eitherhyperglycemia or cardiac ischemia. So QTmax is observed instead ofQTend. As before, data from paced and sensed events should not becombined. QTmax and QTend intervals should be normalized based on heartrate.

Additionally, or in the alternative, values representative ofSTdeviation, QTmax and QTend may be stored for diagnostic purposes. Thedevice may calculate a single value representative of the risk ofhyperglycemia based on a combination of STdeviation, QTmax and QTend,similar to the ischemic burden discussed above. In any case, so long ashyperglycemia is not detected, steps 500-506 are merely repeated. Ifhyperglycemia is detected, however, the patient is warned, at step 508,and, if properly equipped, the device automatically controls therapyappropriate for responding to hyperglycemia. If an insulin pump isimplanted, the pump may be controlled to adjust the dosage of insulin inresponse to hyperglycemia. Techniques set forth in the patentapplication of Kroll, listed above, may be suitable for this purpose.

Hence, FIG. 11 provides an overview of a technique that seeks to detectthe onset of hyperglycemia based on a combination of STdeviation andQTmax. FIG. 12 illustrates changes in ST segment elevation brought on byhyperglycemia. A first exemplary IEGM trace 510 represents a heartbeatof a healthy patient, i.e. one not subject to hypo/hyperglycemia orcardiac ischemia. A second trace 512 illustrates the heartbeat for apatient with hyperglycemia. As with other traces illustrated herein, theIEGM signals of FIG. 12 are exemplary representations of IEGM signalsprovided for illustrative purposes only. Comparing the two traces, theelevation of the ST-segment changes. However, there is little or nochange in QTmax, i.e. an absolute value of ΔQTmax is near zero. (Thereis also little or no change in QTend during hyperglycemia, i.e. anabsolute value of ΔQTend is also near zero.)

Hence, an examination of QTmax allows the device to properly distinguisha change in ST segment elevation due to hyperglycemia from a change dueto hypoglycemia or cardiac ischemia. Compare FIG. 12 with FIGS. 5, 8 and10, described above. Preferably, any changes in ST segment elevation (asderived from sensed events) and QTmax (as derived from sensed events andnormalized based on heart rate) are measured with respect to baselinevalues of those parameters and values for STdeviation and ΔQTmax arecalculated for each heartbeat and averaged over multiple heartbeats. Theaveraged values are compared against respective thresholds. A warning ofhyperglycemia is issued only if STdeviation exceeds its thresholdwhereas ΔQTmax remains below its thresholds. These thresholds may differin value from corresponding thresholds discussed above. The variousthresholds are programmable values set, for example, based uponrespective running averages. Again, multiple thresholds may be defined,in some implementations, to trigger warning signals indicative ofdifferent levels of urgency. Routine experimentation may be performed todetermine appropriate threshold levels.

What have been described thus far are various techniques for detectingcardiac ischemia, hypoglycemia or hyperglycemia based on variouscombinations of QTmax, QTend and STdeviation. Preferably, the device isconfigured to detect any of these conditions and to distinguishtherebetween. This is discussed in the following section.

Combined Hypo/Hyperglycemia and Ischemia Detection Examples

FIG. 13 illustrates an exemplary technique for distinguishing amongcardiac ischemia, hypoglycemia and hyperglycemia wherein QTmax, QTendand STdeviation are each examined. Beginning at step 600, the implanteddevice receives IEGM signals and detect QRS complexes and T-waves. Atstep 602, the device determines ST segment elevation, QTmax and QTendfor each individual heartbeat (as derived from either sensed events onlyor paced events only and properly normalized based on heart rate). Basedupon these values, the device detects and distinguishes between cardiacischemia, hypoglycemia and hyperglycemia. Briefly, at steps 604-606, thedevice detects cardiac ischemia based upon any significant change in STsegment elevation (i.e. a significant value for STdeviation) combinedwith a concurrent shortening of QTmax, so long as there is also littleor no change in QTend. At step 608-610, the device detects hypoglycemiabased upon any significant change in ST segment elevation combined witha lengthening of both QTmax and QTend. At steps 612-614, the devicedetects hyperglycemia based upon a significant change in ST segmentelevation so long as there is little or no change in either QTmax orQTend. Appropriate warning signals are issued upon detection ofischemia, hypoglycemia or hyperglycemia. The above-describedthreshold-based techniques may be employed to make these variousdeterminations. Note that the conditions set forth in the steps 604, 608and 612 are listed above in Table I.

If none of the conditions set forth in steps 604, 608 and 612 are met,then no indication of ischemia, hypoglycemia or hyperglycemia is made,step 616, and processing instead returns to step 604 for examination ofadditional IEGM signals. In other words, no warning of ischemia,hypoglycemia or hyperglycemia is triggered unless each of the threeparameters (STdeviation, QTmax and QTend) corroborates the diagnosis.This differs from the individual examples discussed above wherein anindication of ischemia, hypoglycemia or hyperglycemia may be made basedupon significant changes in only one or two of the parameters. Byexamining all three parameters, a greater degree of reliability andspecificity is achieved. Additional detection parameters may be examinedas well, including otherwise conventional detection parameters or theparameters set forth in the aforementioned patent applications to Wanget al. and Min et al. IN any case, once the analysis is completeappropriate warnings are issued and therapy is adjusted.

FIG. 14 illustrates an exemplary technique for distinguishing amongcardiac ischemia, hypoglycemia and hyperglycemia based on just QTmax andST segment elevation. Beginning at step 700, the implanted deviceevaluates ST segment elevation and ΔQTmax. If there is no substantialchange in ST elevation, i.e. STdeviation is small, then the patient'scondition is deemed to be normal, at step 702. However, if there hasbeen a substantial change in ST elevation, then the device proceeds todetermine whether there has also been a substantial change in QTmax,i.e. whether ΔQTmax exceeds a threshold representative of a significantchange. If not, then hyperglycemia is suggested, at step 704. If ΔQTmaxexceeds the threshold, however, the device determines whether QTmax haslengthened or shortened. If QTmax has lengthened, then hypoglycemia issuggested that step 706. If QTmax has become shorter, then ischemia issuggested that step 708. The above-described threshold-based techniquesmay be employed to make these various determinations. Appropriatewarning signals are issued and therapy is adjusted.

FIG. 15 illustrates an exemplary technique for distinguishing amongcardiac ischemia, hypoglycemia and hyperglycemia based on just QTend andST segment elevation. Beginning at step 800, the implanted deviceevaluates ST segment elevation and ΔQTend. As before, if there is nosubstantial change in ST elevation, i.e. STdeviation is small, then thepatient's condition is deemed to be normal, at step 802. If there hasbeen a substantial change in ST elevation, then the device proceeds todetermine whether there has also been a substantial change in QTend,i.e. whether ΔQTmax exceeds a threshold representative of a significantchange. If not, then ischemia or hyperglycemia are suggested, at step804, and further analysis may need to be performed to distinguishtherebetween (such as by examining QTmax). If ΔQTend exceeds thethreshold, however, the device then determines whether QTend haslengthened or shortened. If QTend has lengthened, then hypoglycemia issuggested that step 806. If QTend has instead become shorter, then theanalysis is indeterminate, at step 808, perhaps indicative of erroneousdata. As already explained, a significant change in ST segment elevationin combination with a significant change in QTend should be associatedwith lengthening of QTend, not a reduction in QTend. Accordingly, nowarnings are issued.) Assuming the analysis is not indeterminate,appropriate warning signals are issued and therapy is adjusted.

What have been described thus far are techniques for distinguishing anddetecting hyperglycemia, hypoglycemia and cardiac ischemia based uponvarious combinations of QTend, QTmax, and ST segment elevation. In thefollowing, an alternative technique particularly for use indistinguishing between hyperglycemia and hypoglycemia will now bedescribed, which is instead based upon an analysis of the amplitudes ofP-waves, QRS complexes, and/or T-waves, or other selected electricalevents.

Overview of Amplitude-Based Technique for Detecting and DistinguishingHypoglycemia and Hyperglycemia

FIG. 16 provides a high-level overview of the amplitude-based techniqueof the invention for detecting and distinguishing hyperglycemia andhypoglycemia. Briefly, at step 900, the pacer/ICD of FIGS. 1-2 (or otherimplantable medical device), detects amplitude-based parametersrepresentative of amplitudes of selected electrical events sensed withinthe heart of the patient in which the pacer/ICD is implanted. Then, atstep 902, the pacer/ICD predicts, detects and distinguishes hypoglycemiaand hyperglycemia from one another based on the amplitude-basedparameter. In an exemplary embodiment, the selected electrical eventsinclude one or more of: P-waves observed within the IEGM, QRS-complexesobserved within the IEGM, and/or T-waves observed within the IEGM. Theamplitude-based parameter detected at step 900 includes one or more of:the absolute value of the event amplitude; the rate of change of theevent amplitude with time; and/or the beat-by-beat change in eventamplitude.

The general technique of detecting and distinguishing hypoglycemia andhyperglycemia based upon the amplitude-based parameters of the cardiacelectrical events may be used in connection with otherhyper/hypoglycemia detection techniques to improve the specificity ofthose techniques, including the techniques described above, as well asthe techniques set forth in the above-reference patents to Kroll andBharmi. Alternatively, various combinations of the amplitude-basedparameters may be used to directly detect hyperglycemia and/orhypoglycemia. This will be a described in greater detail below.

Insofar as hyper/hypoglycemia prediction is concerned, the pacer/ICDincludes components for analyzing trends in amplitude-based data toidentify periods in time when it is statistically likely that an episodeof hyper/hypoglycemia will occur and to issue warning signals in advancethereof. For example, if trend data indicates that the patientfrequently has an episode of hyperglycemia early in the morning and datadetected during a particular morning indicates that atrialdepolarization amplitude is beginning to increase, then a prediction ismade by the pacer/ICD that there is a statistical likelihood that anepisode of hyperglycemia is imminent and warnings are issued. Trend datamay also be used by the physician and patient to aid in the developing astrategy for maintaining glycemic control by, for example, determiningthe optimal times during the day to eat meals or to take insulin. Also,the rate of change of the amplitude values and the dynamics ofseparately obtained glucose and insulin profiles may be exploited toidentify specific ailments. Otherwise conventional predictive techniquesmay be applied by the pacer/ICD to the amplitude-based trend data tomake the predictions.

FIG. 17 provides a stylized representation of an exemplary IEGM signal904 illustrating P-wave amplitude 906, QRS-complex amplitude 908, T-waveamplitude 910. The amplitudes may be measured relative to a baselinesignal voltage 912 detected, as shown, prior to the P-wave (andsubsequent to the T-wave of the preceding cardiac cycle, not separatelyshown.) Since the polarity of the IEGM signal may be arbitrary, theabsolute values of the amplitudes are preferably used. Although theamplitudes of P-waves, QRS-complexes and T-waves are preferablyexploited, the amplitudes of the other electrical events observed withincardiac electrical signals could potentially be exploited as well,assuming that there is a correlation between changes in the amplitudesof those events and the glycemic state of the patient.

Turning now to FIG. 18, an example of the general technique of the FIG.16 will now be described, which exploits P-waves, QRS-complexes andT-waves. Beginning at step 1000, the pacer/ICD of FIGS. 1-2 (or otherimplantable medical device) inputs IEGM signals from the heart of thepatient in which the device is implanted and detects P-waves,QRS-complexes and T-waves within the IEGM signals. Detection of theseelectrical events may be performed using otherwise conventionaldetection techniques. Insofar as the T-wave is concerned, T-wavedetection techniques set forth in the above referenced patentapplications of Min et al. and Wang et al., may be exploited to improveT-wave detection specificity. At step 1002, the pacer/ICD determines theabsolute values of the amplitudes and the rates of change, if any, inthe amplitudes, either is a function of time or beat by beat.

At step 1004, the pacer/ICD then detects the onset of hyperglycemia, ifoccurring within the patient, based on any significant and rapidincrease in P-wave amplitude and any significant and rapid increase inQRS complex amplitude, in combination with a lack of significantincrease in T-wave amplitude. At step 1006, the pacer/ICD detects theonset of hypoglycemia, if occurring within the patient, based on anysignificant and rapid increase in T-wave amplitude along with amoderately rapid increase in QRS complex amplitude to moderatelyelevated levels, in combination with a lack of significant increase inP-wave amplitude.

FIGS. 19-22 illustrate changes in the various amplitude-based parametersoccurring during experimentally induced episodes of hyperglycemia andhypoglycemia within canine test subjects. More specifically, FIG. 19illustrates the changes in blood glucose levels occurring duringepisodes of hyperglycemia and hypoglycemia. A first trace 1008illustrates changes in blood glucose level during an episode ofhyperglycemia induced by infusion of excess blood glucose into anon-diabetic human test subject. The vertical axis of the graphillustrates blood glucose levels in milligrams/deciliter (mg/dL). Ahorizontal axis of graph is a time axis that specifically identifiesvarious points at which blood glucose levels were measured. Point 1represents a baseline blood glucose level, point 2 represents a timeseven minutes from infusion, and point 3 represents a time 17 minutesfrom infusion. As can be seen, there is a significant increase in bloodglucose levels during the first seven minutes, followed by a partialreduction as the test subject's body begins to process the excess bloodglucose levels, i.e. the body's compensatory mechanisms begin to takeeffect. A second trace 1008 of FIG. 19 illustrates changes in bloodglucose level during an episode of hypoglycemia induced by injectingexcess insulin into the same canine test subject. As can be seen, thereis a measurable decrease in blood glucose levels during the first sevenminutes, followed by continued reduction in blood glucose levels overthe next ten minutes, at the additional insulin in the test subject'sbody continues to cause a depletion in blood glucose levels.

FIG. 20 illustrates changes in P-wave amplitude measured during theepisodes of hyperglycemia and hypoglycemia illustrated in FIG. 19. Thevertical axis illustrates the absolute value of the P-wave amplitude inmillivolts (mV). The horizontal time axis illustrates the same points asin FIG. 19. Trace 1012 illustrates changes in P-wave amplitude duringhyperglycemia; whereas trace 1014 illustrates the general lack of changein amplitude during hypoglycemia. As can be seen, there is a significantincrease in P-wave amplitude associated with hyperglycemia, which ismanifested both in terms of a significant increase in the absolute valueof the P-wave amplitude, as well as a rapid rate of change of P-waveamplitude. P-wave amplitude increases, in the example, by nearly 0.8 mVover a period of only seventeen minutes. In contrast, there is little orno change in P-wave amplitude during hypoglycemia. Hence, FIG. 20illustrates that a significant and rapid increase in P-wave amplitude isassociated with hyperglycemia; whereas a lack of change in P-waveamplitude is associated with hypoglycemia.

FIG: 21 illustrates changes in QRS-complex amplitude measured during theepisodes of hyperglycemia and hypoglycemia illustrated in FIG. 19. Thevertical axis illustrates the absolute value of the QRS-complexamplitude in mV. The horizontal time axis illustrates the same points asin FIG. 19. Trace 1016 illustrates changes in QRS-complex amplitudeduring hyperglycemia; whereas trace 1018 illustrates change duringhypoglycemia. As can be seen, there is a significant increase inQRS-complex amplitude associated with hyperglycemia, which is manifestedboth in terms of a significant increase in the absolute value of theQRS-complex amplitude, as well as a rapid rate of change of QRS-complexamplitude. QRS-complex amplitude increases, in the example, by nearly1.0 mV over a period of only 17 minutes. In contrast, there is a lesssignificant increase in QRS-complex amplitude during hypoglycemia, ofless than about 0.6 mV. Hence, FIG. 21 illustrates that a significantand rapid increase in QRS-complex amplitude is associated withhyperglycemia; whereas a more moderate and less rapid increase inQRS-complex amplitude is associated with hypoglycemia.

FIG. 22 illustrates changes in T-wave amplitude measured during theepisodes of hyperglycemia and hypoglycemia illustrated in FIG. 19. Thevertical axis illustrates the absolute value of the T-wave amplitude inmV. The horizontal time axis again illustrates the same points as inFIG. 19. Trace 1020 illustrates changes in T-wave amplitude duringhyperglycemia; whereas trace 1022 illustrates changes duringhypoglycemia. As can be seen, there is a significant increase in T-waveamplitude associated with hypoglycemia, which is manifested both interms of a significant increase in the absolute value of the T-waveamplitude, as well as a rapid rate of change of T-wave amplitude. T-waveamplitude increases, in the example, by nearly 1.0 mV over a period ofonly seventeen minutes. In contrast, there is little or no change inT-wave amplitude during hyperglycemia. More specifically, there is aslight increase in T-wave amplitude observed at the seven minute markduring hyperglycemia, followed by a reduction back to baseline levelsover the next ten minutes. Hence, FIG. 22 illustrates that a significantand rapid increase in T-wave amplitude is associated with hypoglycemia;whereas a general lack of change in T-wave amplitude is associated withhyperglycemia.

Thus, FIGS. 19-22 illustrate changes in amplitudes of P-waves,QRS-complexes and T-waves within canine test subjects arising as aresult of changes in the glycemic state of test subject. It is believedthat similar changes occur in humans. For the purposes of the invention,a significant increase in an amplitude value may be detected bycomparing current amplitude values against running averages of previousamplitude values to determine differences therebetween, which are thencompared against predetermined threshold values indicative of the onsetof hyperglycemia or hypoglycemia. In this regard, separate amplitudethreshold values are predetermined for P-wave amplitude, QRS-complexamplitude, and T-wave amplitude. Insofar as hyperglycemia is concerned,the amplitude threshold values for P-wave amplitude and QRS complexamplitude represent upper thresholds, above which hyperglycemia isindicated. The amplitude threshold value for T-wave amplitude representsa lower threshold, below which hyperglycemia is confirmed. Insofar ashypoglycemia is concerned, the rate threshold values for T-waveamplitude represents an upper threshold, above which hypoglycemia isindicated. The amplitude threshold value for P-wave amplitude representsa lower threshold, below which hypoglycemia is confirmed. Forhypoglycemia, the amplitude threshold value for the QRS-complexamplitude represents an intermediate threshold. If the QRS-complexamplitude exceeds the intermediate hypoglycemia threshold but not theupper hyperglycemia threshold, then hypoglycemia is indicated. If theQRS-complex amplitude exceeds both intermediate hypoglycemia thresholdand the upper hyperglycemia threshold, then hyperglycemia is insteadindicated.

A rapid increase in the amplitude value of an electrical event (such asthe P-wave) may be detected by calculating the rate of change ofamplitude values (either as a function of time or as a beat by beatchange), then comparing the rate of change against predeterminedthreshold values indicative of the onset of hyperglycemia orhypoglycemia. Again, separate rate threshold values are predeterminedfor P-wave amplitude changes, QRS-complex amplitude changes and T-waveamplitude changes. Given that hyperglycemia is associated with a lack ofsignificant increase in T-wave amplitude, it is unnecessary to calculatea rate of change in T-wave amplitude for the purposes of confirminghyperglycemia. Likewise, given that hypoglycemia is associated with alack of significant increase in P-wave amplitude, it is unnecessary tocalculate a rate of change in P-wave amplitude for the purposes ofconfirming hypoglycemia.

Preferably, the various amplitude-based threshold values are expressedas percentages of the running average values. In one example, anincrease of over a predetermined upper threshold percentage of therunning average of a given amplitude parameter (such as P-wave amplitudeor T-wave amplitude) is deemed to represent a significant increase. Anincrease of over predetermined intermediate threshold percentage of therunning average of a given amplitude parameter (such as the QRS-complexamplitude) is deemed to represent a moderate increase. An increase ofless than predetermined lower threshold percentage over the runningaverage is deemed to be indicative of lack of increase. Likewise,preferably, the rate-based threshold values are expressed as percentvalues.

Appropriate values for the various thresholds used for detecting anddistinguishing hyperglycemia and hypoglycemia may be determined inadvance through otherwise routine experimentation. For example, studiesmay be performed for various classes of patients (based on, for example,gender, age, medical condition, weight, etc.) to determine thresholdvalues that may be appropriate for use with those classes of patients.Following implant of the pacer/ICD, a physician or other medicalprofessional inputs the age, gender, weight, etc. for the patient intothe external programmer, which then looks up the appropriate thresholdvalues from tables stored therein and transmits those values to thepacer/ICD for use therein. Alternatively, the threshold values may beindividually set for particular patients. In one example, the physicianbriefly induces episodes of hyperglycemia and hypoglycemia within thepatient and records and monitors changes in the various amplitudevalues, from which suitable threshold values for use with thatparticular patient are then derived. The threshold values are thenprogrammed into the pacer/ICD of the particular patient via the externalprogrammer device.

In any case, if hyperglycemia is indicated then, step 1024 of FIG. 18 isperformed wherein the pacer/ICD responds to the newly detected episodeof hyperglycemia. The specific response depends upon the capabilities ofthe implanted system and the needs of the particular patient. If insulinis being automatically delivered to an insulin-dependent diabetic via animplantable drug pump then delivery of insulin is increased in responseto hyperglycemia. Preferably, any hyperglycemia-related conditions ofthe patient (such as diabetes) are diagnosed in advance by the physicianand the resulting diagnosis is programmed into the implanted pacer/ICDby the physician for use in controlling therapy. At step 1024,appropriate warning signals are generated via an implanted warningdevice or external bedside monitor. Such warning signals areparticularly desirable within implantable systems not equipped toprovide any automatic hyperglycemia therapy. For example, if patient isan insulin-dependent diabetic, but no implantable insulin pump isprovided, then warning signals are provided to alert the patient tomanually take insulin.

Preferably, the warning signals are of sufficient magnitude to awakenthe patient, if sleeping. The magnitude of the warning signals may becontrolled based upon the time of day or the activity state of thepatient so as to be of greater magnitude if the patient appears to beresting or sleeping. Otherwise conventional sleep detectors may also beemployed in this regard. In one example, once a subcutaneous warningsignal is perceived, the patient positions an external warning deviceabove his or her chest. The handheld device receives the short-rangetelemetry signals and provides audible or visual verification of thewarning signal. The handheld warning device thereby providesconfirmation of the warning to the patient, who may be otherwiseuncertain as to the reason for the internally generated warning signal.Upon confirmation of the warning, the patient then takes appropriateactions, such as taking insulin. Warning devices of this type arediscussed in U.S. patent application Ser. No. 10/603,429, of Wang etal., entitled “System and Method for Detecting Cardiac Ischemia Using anImplantable Medical Device.” Also, preferably, any warning signalstransmitted to a bedside monitor are then conveyed to medical personalvia any suitable communication network, particularly if the patient isin a hospital, rest home or the like where medical personnel can easilysummoned.

If hypoglycemia is instead indicated then, step 1026 of FIG. 18 isperformed wherein the pacer/ICD responds to the episode of hypoglycemia.Again, the specific response depends upon the capabilities of theimplanted system and the needs of the particular patient. If insulin isbeing automatically delivered to an insulin-dependent diabetic via animplantable drug pump then delivery of insulin is suspended so as toprevent additional insulin from exacerbating the hypoglycemia. On theother hand, if the patient has been diagnosed with hyperinsulinism,delivery of appropriate medications such as sulfonylureas, meglitinides,biguanides, thiazolidinediones, or alpha glucosidase inhibitors, may beinitiated using an implantable drug pump (assuming such drugs aresuitable for automatic delivery via a drug pump.) At step 1026, thepacer/ICD also preferably begins charging its defibrillation capacitorsin expectation of delivery of shocks in the event that the episode ofhypoglycemia triggers ventricular fibrillation. Appropriate warningsignals are generated via an implanted warning device or externalbedside monitor. Such warning signals are particularly desirable withinimplantable systems not equipped to provide any automatic hypoglycemiatherapy. For example, if patient is an insulin-dependent diabetic, thenwarning signals are provided to alert the patient to take a suitablenumber of sugar pills or other substances or medications sufficientincrease blood glucose levels.

Note that, typically, the detection of hyper/hypoglycemia is disabledduring an arrhythmia as some arrhythmias may affect the relativeamplitudes of the various cardiac electrical events so as to preventreliable detection of hyper/hypoglycemia.

Also, note that, in many cases, a detectable change in theamplitude-based parameters analyzed in accordance with the inventionoccurs even before an episode of hyper/hypoglycemia actually begins,thus allowing for prediction of the episode and allowing for an earlywarning to be issued to the patient.

Thus, FIG. 18 illustrates an exemplary method for detecting anddistinguishing hyperglycemia and hypoglycemia. Depending upon theparticular implementation, the pacer/ICD may be configured just todistinguish between hyperglycemia and hypoglycemia as an adjunct toother hyper/hypoglycemia techniques, such as those described above withreferences to of FIGS. 1-18. For example, the pacer/ICD may beprogrammed merely to analyze P-wave amplitudes as a means fordistinguishing hyperglycemia from hypoglycemia so as to improve thespecificity of another glycemic state detection technique. In otherexamples, pacer/ICD may be programmed merely to analyze P-waveamplitudes or QRS-complex amplitudes to improve the specificity of otherdetection techniques. In general, any of the individual parametersdiscussed with reference to FIG. 18 may be employed to aid indistinguishing hyperglycemia from hypoglycemia. Hence, it is notnecessary for the pacer/ICD to detect or analyze all of theabove-described parameters. In some cases, only a single parameter isanalyzed to aid in distinguishing hyperglycemia and hypoglycemia. Inother cases, two or more parameters are analyzed. As already denoted, ananalysis of P-wave amplitudes in combination with T-wave amplitude isparticularly effective for use in distinguishing hyperglycemia fromhypoglycemia, since P-waves and T-waves respond oppositely tohyperglycemia and hypoglycemia.

In other implementations, however, the pacer/ICD is programmed todirectly detect hyperglycemia and/or hypoglycemia based upon variouscombinations of the aforementioned parameters. In other words, thetechniques described herein are not merely used as an aid indistinguishing hyperglycemia from hypoglycemia, but are instead used todirectly detect such conditions. In particular, a significant increasein P-wave amplitude and/or a significant increase into QRS-complexamplitude, in combination with a lack of significant change in T-waveamplitude is sufficient to detect the onset of hyperglycemia. Improvedspecificity may be achieved by examining both P-wave amplitude andQRS-complex amplitude, though only one or the other is typicallysufficient within most patients. Insofar as hypoglycemia is concerned, asignificant increase in T-wave amplitude in combination with a lack ofchange in P-wave amplitude is sufficient to detect the onset ofhypoglycemia. Improved specificity may be achieved by additionallyexamining QRS-complex amplitudes to verify that the QRS-complexamplitude exhibits a moderate increase.

In general, a wide variety of techniques can be implemented consistentwith the principles the invention and no attempt is made herein todescribe all possible techniques. Although described primarily withreference to an example wherein the implanted device is adefibrillation/pacer, principles of the invention are applicable toother implantable medical devices as well. In addition, whereas thetechniques described herein are performed by the implanted device, thetechniques may alternatively be performed by an external device usingIEGM signals or other signals transmitted from the implanted device. Forexample, a bedside monitor may be configured to receive IEGM signalsfrom the implanted device via “long-range” telemetry then analyze thesignals using the aforementioned techniques and issue any appropriatewarnings. Alternatively, the bedside monitor may transmit the IEGM datato a central server or other central processing device, which analyzesdata from multiple patients to detect ischemia, hypoglycemia orhyperglycemia within any of those patients. In such an implementation,the central processing device then transmits appropriate warning signalsto the bedside monitor of the patient for warning the patient and thenadditionally transmits appropriate warning signals to the physicianassociated with the patient or a third party such as emergency medicalservice (EMS) personnel. A system incorporating bedside monitoring unitsconnected to a centralized external programmer system is described inU.S. Patent Application Serial Number 2002/0143372, of Snell et al.,entitled “System and Method for Remote Programming of ImplantableCardiac Stimulation Devices”, published Oct. 3, 2002.

The various functional components of the exemplary systems describedherein may be implemented using any appropriate technology including,for example, microprocessors running software programs or applicationspecific integrated circuits (ASICs) executing hard-wired logicoperations. In general, while the invention has been described withreference to particular embodiments, modifications can be made theretowithout departing from the spirit and scope of the invention. Note alsothat the term “including” as used herein is intended to be inclusive,i.e. “including but not limited to.”

1. A method for use with an implantable medical device fordistinguishing between hypoglycemia and hyperglycemia within a patientin which the device is implanted, the method comprising: detecting anamplitude-based parameter representative of an amplitude of one or moreselected electrical events of the heart; and distinguishing hypoglycemiaand hyperglycemia from one another based on the amplitude-basedparameter.
 2. The method of claim 1 wherein detecting an amplitude-basedparameter representative of amplitudes of electrical events sensedwithin the heart of the patient is performed in response to one or moreof: atrial depolarization events, ventricular depolarization events, andventricular repolarization events.
 3. The method of claim 1 whereindetecting an amplitude-based parameter representative of amplitudes ofelectrical events sensed within the heart of the patient is performed into detect one or more of: the absolute values of the amplitudes of theelectrical events; a rate of change in the amplitudes of the electricalevents over time; or a rate of change in the amplitudes of theelectrical events over time.
 4. The method of claim 1 wherein detectingthe amplitude-based parameter is performed to detect absolute values ofthe amplitudes of atrial depolarization events; and whereindistinguishing hypoglycemia and hyperglycemia from one another based isperformed to associate a significant increase in the absolute value ofthe amplitudes of the atrial depolarization events with hyperglycemia.5. The method of claim 1 wherein detecting the amplitude-based parameteris performed to detect a rate of change in the amplitudes of atrialdepolarization events over time; and wherein distinguishing hypoglycemiaand hyperglycemia from one another based on the amplitude-basedparameter is performed to associate a significant rate of change in theamplitudes of the atrial depolarization events over time withhyperglycemia.
 6. The method of claim 1 wherein detecting theamplitude-based parameter is performed to detect a change in theamplitudes of atrial depolarization events from beat to beat; andwherein distinguishing hypoglycemia and hyperglycemia from one anotherbased on the amplitude-based parameter is performed to associate asignificant change in the amplitudes of the atrial depolarization eventsfrom beat to beat with hyperglycemia.
 7. The method of claim 1 whereindetecting the amplitude-based parameter is performed to detect absolutevalues of the amplitudes of ventricular depolarization events; andwherein distinguishing hypoglycemia and hyperglycemia from one anotherbased is performed to associate a more significant increase in theabsolute value of the amplitudes of the ventricular depolarizationevents with hyperglycemia than with hypoglycemia.
 8. The method of claim1 wherein detecting the amplitude-based parameter is performed to detecta rate of change in the amplitudes of ventricular depolarization eventsover time; and wherein distinguishing hypoglycemia and hyperglycemiafrom one another based on the amplitude-based parameter is performed toassociate a faster rate of change in the amplitudes of the ventriculardepolarization events over time with hyperglycemia than withhypoglycemia.
 9. The method of claim 1 wherein detecting theamplitude-based parameter is performed to detect a change in theamplitudes of ventricular depolarization events from beat to beat; andwherein distinguishing hypoglycemia and hyperglycemia from one anotherbased on the amplitude-based parameter is performed to associate fasterrate of change in the amplitudes of the ventricular depolarizationevents from beat to beat with hyperglycemia than with hypoglycemia. 10.The method of claim 1 wherein detecting the amplitude-based parameter isperformed to detect absolute values of the amplitudes of ventricularrepolarization events; and wherein distinguishing hypoglycemia andhyperglycemia from one another based is performed to associate asignificant increase in the absolute value of the amplitudes of theventricular repolarization events with hypoglycemia.
 11. The method ofclaim 1 wherein detecting the amplitude-based parameter is performed todetect a rate of change in the amplitudes of ventricular repolarizationevents over time; and wherein distinguishing hypoglycemia andhyperglycemia from one another based on the amplitude-based parameter isperformed to associate a significant rate of change in the amplitudes ofthe atrial depolarization events over time with hypoglycemia.
 12. Themethod of claim 1 wherein detecting the amplitude-based parameter isperformed to detect a change in the amplitudes of ventricularrepolarization events from beat to beat; and wherein distinguishinghypoglycemia and hyperglycemia from one another based on theamplitude-based parameter is performed to associate a significant changein the amplitudes of the ventricular repolarization events from beat tobeat with hypoglycemia.
 13. The method of claim 1 further comprisingcontrolling therapy based on whether the patient is subject tohypoglycemia or hyperglycemia.
 14. The method of claim 13 wherein animplantable drug pump is provided for delivering insulin and wherein, ifthe patient is subject to hypoglycemia, controlling therapy comprisesreducing insulin delivery to the patient using the insulin pump.
 15. Themethod of claim 13 wherein an implantable insulin pump is provided andwherein, if the patient is subject to hyperglycemia, controlling therapycomprises increasing insulin delivery to the patient using the insulinpump.
 16. The method of claim 1 further comprising generating a warningsignal.
 17. The method of claim 1 wherein the implantable device includea defibrillator with defibrillation shock capacitors and wherein, if thepatient is subject to hypoglycemia, the method further comprisescharging the capacitors.
 18. The method of claim 1 further comprisingrecording diagnostic information based on whether the patient is subjectto hypoglycemia or hyperglycemia.
 19. The method of claim 18 furthercomprising examining the recorded diagnostic information to predictepisodes of hypoglycemia or hyperglycemia.
 20. The method of claim 19wherein examining the recorded diagnostic information to predictepisodes of hypoglycemia or hyperglycemia is performed by identifying atrend in the amplitude-based parameter.
 21. The method of claim 20further comprising issuing a warning signal upon prediction of anepisode of hypoglycemia or hyperglycemia.
 22. An implantable medicaldevice for distinguishing between hypoglycemia and hyperglycemia,comprising: an electrical event detector operative to detect anamplitude-based parameter representative of amplitudes of one or moreselected electrical events of the heart; and ahypoglycemia/hyperglycemia distinguishing unit operative to distinguishhypoglycemia and hyperglycemia from one another based on theamplitude-based parameter.
 23. A system for use with an implantablemedical device for distinguishing between hypoglycemia and hyperglycemiawithin a patient in which the device is implanted, comprising: means fordetecting an amplitude-based parameter of one or more selectedelectrical events of the heart; and means for distinguishinghypoglycemia from hyperglycemia based on the amplitude-based parameter.